Substituted diamino-carboxamide and diamino-carbonitrile pyrimidine derivatives, their compositions and methods of treatment using them

This document describes some diaminokarboksamidnye and diaminokarbonitrilnye derivatives of pyrimidine compounds, compositions comprising an effective amount of such compounds, and methods of treating or preventing a liver fibrotic diseases or conditions the treatment or prevention of which are possible due to inhibition path JNK, comprising administering an effective amount of such diaminokarboksamidnyh and diaminokarbonitrilnyh pyrimidine derivatives of compounds of the individual in need thereof.

TECHNICAL FIELD

The connection between abnormal protein phosphorylation and the cause or consequence of diseases has been known for over 20 years. Therefore, protein kinase become a very important group of drug targets. [Cm. Cohen, Nature, 1: 309-315 (2002), Gaestel et al. Curr.Med.Chem. 14: 2214-223 (2007); Grimminger et al. Nat. Rev. Drug Disc. 9 (12): 956-970 (2010)]. Various protein kinase inhibitors have been used in clinical practice for treating shirogo range of diseases such as cancer and chronic inflammatory diseases, including rheumatoid arthritis and psoriasis. [Cm. Cohen, Eur. J. Biochem, 268: 5001-5010 (2001). Protein Kinase Inhibitors for the Treatment of Disease: The Promise and the Problems, Handbook of Experimental Pharmacology, Springer Berlin Heidelberg, 167 (2005)].

JNK is a ubiquitously expressed serine / threonine kinase that belongs together with the ERK (kinase, extracellular signal-regulated) and p38, a family of mitogen-activated protein kinase (MAPK). [Kyriakis JM, Sci. STKE (48): pe1 (2000); Whitmarsh AJ, et al. Sci. STKE (1): pe1 (1999); Schramek H, News Physiol. Sci. 17: 62-7 (2002); Ichijo H, Oncogene 18 (45): 6087-93 (1999)]. MAPK are important mediators of signal transmission from the cell surface to the nucleus by using a cascade of phosphorylation for coordinated cellular response to external stimuli selected by phosphorylation of intracellular proteins, including transcription factors. In addition, JNK also phosphorylates non-nuclear proteins, for example, representatives of the families of IRS-1 and Bcl-2. [Davis RJ, Trends Biochem. Sci. 9 (11): 470-473 (1994); Seger R et al., FASEB J .; 9 (9): 726-35 (1995);

Mitogen-activated protein kinase (MAP) is involved in transmission of signals to the nucleus of cells in response to extracellular stimuli. Examples of kinases MAP of isomers ERK p38 and JNK include, but are not limited to, mitogen-activated protein kinase 1 (ERK2), mitogen-activated protein kinase 8 (JNK1), mitogen-activated protein kinase 9 (MAPK9 or JNK2), mitogen-activated protein kinase 10 (MAPK10 or JNK3) and mitogen-activated protein kinase 14 (MAPK14 or p38alpha). MAP kinases are a family of proline-directed serine / threonine kinases that mediate signal transduction from extracellular receptors or proteins hits shock, osmotic stress, oxidative active forms (ROS) or UV-radiation. [See., Sridhar et al., Pharmaceutical Research, 17:11 1345-1353 (2000)]. MAP kinase activated by phosphorylation of threonine and tyrosine via bispecific protein kinase kinases MKK and including MEKK, further arranged in the signal path. As shown, cell proliferation and differentiation are under the regulatory control of the plurality of MAP kinase cascades. [cm. Sridhar et al., Pharmaceutical Research, 17:11 1345-1353 (2000)]. By itself, MAP kinase pathway plays a role in a large number of disease states. For example, it was shown, that defects in MAP kinase activity lead to abnormal cell proliferation and to the emergence of malignancies. [See., Hu et al., Cell Growth Differ. 11: 191-200 (2000); and Das et al., Breast Cancer Res. Treat. 40: 141 (1996)]. Moreover, MAP kinase activity is involved in the insulin resistance associated with type 2 diabetes [see., Virkamaki et al., J. Clin. Invest. 103: 931-943 (1999)] and obesity. Changes in insulin resistance may have a direct effect on glucose and lipid metabolism in the liver, making contribution to the development of steatosis, which can progress to liver fibrosis [Vallerie et al. Science Translational Medicine 2 (60): 1-7 (2010)].

Steatosis can develop in the presence of either saturated or unsaturated free fatty acid (FFA). FFA promotes persistent activation of JNK in the liver and excessive concentration of FFA may lead to apoptosis of hepatocytes. It reported that mouse JNK2 - / - partially protected from apoptosis due steatosis and saturated FFA (e.g., stearic acid), but the protection is not associated with an unsaturated FFA [Malhi et al. J. Biol. 281: 12093-12101 (2006)]. Mouse JNK1 - / - are protected from destruction caused by FFA. Role of JNK1 and JNK2 was examined in mice fed a CDAA, whose progression was observed to seatogepatita steatosis and then to gepatofibroza [Kodama et al, Gastroenterology 137:. 1467-1477 (2009)]. While both mice, JNK1 - / - and JNK2 - / -, developed steatosis, mouse JNK1 - / -, but not myshy JNK2 - / -, showed considerable resistance to progression to fibrosis and hepatitis. Chimeric mice with deletion JNK1 - / -, limited bone marrow cells also exhibited resistance to hepatitis and fibrosis associated with activation of Kupffer cells as a key factor of initiating steatosis progression. Certainly, macrophages JNK1 - / - do not express IL-1, IL-6, TNF and NO in response to LPS [Sanchez-Tillo et al, J Biol Chem.. 282 (17): 12566-73 (2007)], and in Kupffer cells derived from JNK1 - / - mice or wild type mice, and treated with inhibitor JNK, SP600125, decrease expression of TNF was observed, IL-6 and IL 1 in response to LPS [Kodama et al, Gastroenterology 137:. 1467-1477 (2009)]. also exhibited resistance to hepatitis and fibrosis associated with activation of Kupffer cells as a key factor of initiating steatosis progression. Certainly, macrophages JNK1 - / - do not express IL-1, IL-6, TNF and NO in response to LPS [Sanchez-Tillo et al, J Biol Chem.. 282 (17): 12566-73 (2007)], and in Kupffer cells derived from JNK1 - / - mice or wild type mice, and treated with inhibitor JNK, SP600125, decrease expression of TNF was observed, IL-6 and IL 1 in response to LPS [Kodama et al, Gastroenterology 137:. 1467-1477 (2009)]. also exhibited resistance to hepatitis and fibrosis associated with activation of Kupffer cells as a key factor of initiating steatosis progression. Certainly, macrophages JNK1 - / - do not express IL-1, IL-6, TNF and NO in response to LPS [Sanchez-Tillo et al, J Biol Chem.. 282 (17): 12566-73 (2007)], and in Kupffer cells derived from JNK1 - / - mice or wild type mice, and treated with inhibitor JNK, SP600125, decrease expression of TNF was observed, IL-6 and IL 1 in response to LPS [Kodama et al, Gastroenterology 137:. 1467-1477 (2009)].

Knowing all the labyrinth pathways of protein kinases and complexities interconnections and interactions of various protein kinases and kinase pathways is the main important task in the development of pharmaceutical agents capable of acting as protein kinase modulators, regulators or inhibitors that are effective on various kinases or multiple kinase pathways. Thus, there remains a need for new kinase modulators and, in particular modulators JNK.

Indication or identification of any reference in Section 2 of this description should not be construed that the reference is a reference to the prior art.

Short description

As used herein, discloses compounds of the following formula (I):

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and their pharmaceutically acceptable salts, tautomers, isotopologues, stereoisomers and prodrugs thereof, wherein R¹ and R² as defined herein.

In the present specification discloses the following compounds of formula (IB):

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and their pharmaceutically acceptable salts, tautomers, isotopologues, stereoisomers and prodrugs thereof, wherein R³ and R⁴ as defined herein.

A compound of formula (I) or formula (IB) or a pharmaceutically acceptable salt, tautomer, isotopologue, stereoisomer or prodrug thereof (each designated herein as "diaminopirimidinovoe compound") can be used for the treatment or prevention of liver fibrotic diseases or diabetes and / or metabolic syndrome, which lead to the development of fibrotic liver diseases as described herein. In another aspect, diaminopirimidinovoe compound can be used for treating or preventing a condition the treatment or prevention of which can be by way of inhibiting JNK, as described herein.

In one aspect, disclosed herein diaminopirimidinovye compounds such as, for example, in Tables 1, 2 and 3 (see. The end of the description).

In one aspect, the present specification discloses pharmaceutical compositions comprising an effective amount diaminopirimidinovogo compound described herein and a pharmaceutically acceptable carrier, excipient or filler. In some embodiments, the pharmaceutical composition is suitable for oral, parenteral, transmucosal, transdermal administration or for local application.

In one aspect, the present specification discloses methods for the treatment or prevention of liver fibrotic diseases such as NASH, steatosis, cirrhosis, primary sclerosing cholangitis, primary biliary cirrhosis, hepatitis, hepatocellular carcinoma and liver fibrosis associated with chronic or recurrent alcohol use infection, a liver transplant or a liver disease caused by the intake of drugs which comprise administering to an individual an effective amount of diamino irimidinovogo compound described herein; and a pharmaceutically acceptable carrier, excipient or filler. In another aspect, the present description discloses methods for treating or preventing diabetes or metabolic syndrome, which lead to the development of fibrotic liver diseases such as non-alcoholic steatohepatitis, steatosis, hepatitis, or cirrhosis, comprising administering to an individual in need an effective amount of a compound diaminopirimidinovogo. Furthermore, in the present specification provides methods of treating or preventing a condition the treatment or prevention of which is carried out by way of inhibition of JNK, comprising administering to an individual in need an effective amount diaminopirimidinovogo compound described herein; and a pharmaceutically acceptable carrier, excipient or filler. treatment or prevention of which is carried out by way of inhibition of JNK, comprising administering to an individual in need an effective amount diaminopirimidinovogo compound described herein; and a pharmaceutically acceptable carrier, excipient or filler. treatment or prevention of which is carried out by way of inhibition of JNK, comprising administering to an individual in need an effective amount diaminopirimidinovogo compound described herein; and a pharmaceutically acceptable carrier, excipient or filler.

In one aspect, the herein disclosed methods for inhibiting a kinase, e.g., JNK1, JNK2 or both of these kinases, in a cell expressing said kinase, which comprise bringing said cell into contact with an effective amount diaminopirimidinovogo compound described herein.

In another aspect, the present specification discloses methods for preparing diaminopirimidinovyh compounds described herein.

These embodiments may be better understood when sending to the "Detailed Description" and "Examples", which are intended to illustrate embodiments of unbounded.

Detailed description

define

"Alkyl" group is a saturated, partially saturated or unsaturated, straight or branched chain acyclic hydrocarbons with 1-10 carbon atoms, typically 1-8 carbons or, in some embodiments, 1-6, 1-4 or 2-6 or carbon atoms. Examples of alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl and -n-hexyl; while saturated branched alkyls include -isopropyl, -sec-butyl, -izobutil, -tert-butyl, -izopentil, -neopentil, tert-pentyl, -2-methylpentyl, -3-methylpentyl, -4-methylpentyl, -2, 3-dimethylbutyl and the like. Examples of unsaturated alkyl groups, among others, include, but are not limited to, vinyl, allyl, -CH = CH (CH₃), -CH=C(CH₃)₂, -C(CH₃)=CH₂, -C(CH₃) = CH (CH₃), -C(CH₂CH₃)=CH₂, -C≡CH, -C≡C(CH₃), -C≡C(CH₂CH₃), -CH₂C≡CH, -CH₂C≡C(CH₃) и -CH₂C≡C(CH₇CH₃). The alkyl group may be substituted or unsubstituted. If the alkyl groups described herein are specified - "substituted," they may be substituted with any substituent or substituents that can be found in the examples of the compounds and embodiments described herein, as well as halogen (chloro, iodo , bromo or fluoro); alkyl; hydroxy; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioester; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfonyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxylamine; alkoxyamine; aralkoksiaminom; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; B (OH)₂ or O (alkyl) aminocarbonyl.

"Cycloalkyl" group is a saturated, partially saturated or unsaturated cyclic alkyl group having 3-10 carbon atoms having a single cyclic ring or multiple condensed or bridged rings which can be optionally substituted with 1-3 alkyl groups. In some embodiments, the cycloalkyl groups have 3-8 ring members, whereas in other embodiments the number of ring carbon atoms is in the range of 3-5, 3-6 or 3-7. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-metiltsiklooktil, and the like, or multiple ring structures or ring structures bridged, such as the 1-bicyclo [1.1.1] pentyl, bicyclo [2.1.1] geksil, bicyclo [2.2.1] geptil, bicyclo [2.2.2] octyl, adamantyl, and the like In addition. Examples nenasyŝennyh cikloalkilʹnyh groups, amid pročego, include ciklogeksenil, cyclopentenyl, ciklogeksadienil, butadienyl, pentadienyl, geksadienil. Cikloalkilʹnaâ group can be zameŝennoj or nezameŝennoj. Such zameŝennye cikloalkilʹnye groups include, in As an example, the fact ciklogeksanol and the like.

An "aryl" group is an aromatic carbocyclic group having 6-14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). In some embodiments, aryl groups contain 6-14 carbons, and in others - 6-12 or even 6-10 carbon atoms in the ring of the group. Specific examples of aryls include phenyl, biphenyl, naphthyl and the like. The aryl group may be substituted or unsubstituted. The phrase "aryl groups" also includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl and the like).

"Heteroaryl" group is an aryl ring system having from one to four heteroatoms in the ring atoms in a heteroaromatic ring system, wherein the remaining atoms are carbon atoms. In some embodiments, heteroaryl groups contain 3-6 ring atoms, in others - 6-9 or 6-10 atoms in the ring of the group. Suitable heteroatoms include oxygen, sulfur and azot.V some embodiments, the heteroaryl ring system is monocyclic or bicyclic. Non-limiting examples include, but are not limited to, groups such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (eg, benzo [d] isoxazolyl), thiazolyl, pyrolyl, pyridazinyl, pyrimidyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl (e.g., indolyl-2-onyl or isoindolin-1-onyl), azaindolyl (pirrolopiridil or 1H-pyrrole [2,3-b] pyridyl), indazolyl, benzimidazolyl (e.g., 1H-benzo [d] imidazolyl), imidazopyridyl (e.g., azabenzimidazole or 1H-imidazo [4,5-b] pyridyl) pirazolopiridil, triazolopiridil, benzotriazolyl (e.g., 1H-benzo [d] [1.2.3] triazolyl), benzoxazolyl (e.g., benzo [d] oxazolyl) , benzothiazolyl, benzothiadiazolyl, izoksazolopiridil, tianaftalenil, purinyl, Xanthine, adenine, guanine, quinolinyl, isoquinolinyl (for example, 3,4-digidroizohinolin-1 (2H) -onyl), tetra agidrohinolinil, quinoxalinyl and quinazolinyl.

"Heterocyclyl" is an aromatic (also denoted as heteroaryl) or non-aromatic cycloalkyl in which one to four of the ring carbon atoms are independently replaced by a heteroatom from the group consisting of O, S and N. In some embodiments, heterocyclyl groups include 3-10 members ring, while the other groups have 3-5, 3-6 or 3-8 ring members. Heterocyclyls may be linked to other groups at any ring atom (i.e., any carbon atom or heteroatom of the heterocyclic ring). Heterocycloalkyl group may be substituted or unsubstituted. Heterocyclyl groups include unsaturated, partially saturated and saturated ring systems such as, for example, imidazolyl, imidazolinyl and imidazolidinyl (e.g., imidazolidin-4-one or imidazolidine-2,4-dione) group. terms heterocyclyl includes fused ring types, including those comprising fused aromatic and nonaromatic groups such as, e.g., 1- and 2-aminotetralin, benzotriazolyl (e.g., 1H-benzo [d] [1,2,3] triazolyl), benzimidazolyl (e.g., 1H-benzo [d] imidazolyl), 2,3-dihydrobenzo [1,4] dioxinyl and benzo [1.3] dioxolyl. The phrase also includes polycyclic ring systems bridged containing a heteroatom such as, but not limited to, hinuklidil. Representative examples of heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, azepanyl, oxetanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dione), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo [d] isoxazolyl), thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl (e.g., piperazine-2-onyl), morpholinyl, thiomorpholinyl, tetragidropiranil (e.g. tetragidro-2H-pyranyl), tetragidrotiopiranil, oxathianyl, dioxane, dithianyl, pyranyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, digidropiridil, digidroditiinil, digidroditionil, 1,4-dioxaspiro [4.5] decanyl, gomopiperazinil, quinuclidyl , indolyl (of example, indolyl-2-onyl or isoindolin-1-onyl), indolinyl, isoindolyl, isoindolinyl, azaindolyl (pirrolopiridil or 1H-pyrrole [2,3-b] pyridyl), indazolyl, indolizinyl, benzotriazolyl (e.g., 1H-benzo [ d] [1,2,3] triazolyl), benzimidazolyl (e.g. 1H-benzo [d] imidazolyl or 1H-benzo [d] imidazol-2 (3H) -only), benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl (it is truly meet, benzo [d] oxazolyl ), benzothiazolyl, benzothiadiazolyl, benzo [1,3] dioxolyl, pirazolopiridil (e.g., 1H-pyrazolo [3,4-b] pyridyl, 1H-pyrazolo [4,3-b] pyridyl), imidazopyridyl (e.g., 1H azabenzimidazole or -imidazo [4,5-b] pyridyl), triazolopiridil, izoksazolopiridil, purinyl, Xanthine, adenine, guanine, quinolinyl, isoquinolinyl (for example, 3,4-digidroizohino lin-1 (2H) -onyl), quinolizinyl, quinoxalinyl, quinazolinyl, tsinnolinil, phthalazinyl, naphthyridinyl, pteridinyl, tianaftalenil, digidrobenzotiazinil, digidrobenzofuranil, digidroindolil, digidrobenzodioksinil, tetragidroindolil, tetragidroindazolil, tetragidrobenzimidazolil, tetragidrobenzotriazolil, tetragidropirrolopiridil, tetragidropirazolopiridil, tetragidroimidazopiridil, tetragidrotriazolopiridil, tetrahydropyrimidin-2 (1H) -one and tetrahydroquinolinyl. Typical non-aromatic heterocyclyl group include fused ring not types which contain condensed aromatic group. Examples of non-aromatic heterocyclyl groups include aziridinyl, azetidinyl, azepanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dione), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, piperidyl, piperazinyl (e.g., piperazin-2- onyl), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g. tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathiane, dithianyl, 1,4-dioxaspiro [4.5] decanyl, homopiperazinyl, or hinuklidil tetrahydropyrimidin-2 (1H) -one.

"Cycloalkylalkyl" is a radical group of the formula -alkyl-cycloalkyl, where alkyl and cycloalkyl are as defined above. Substituted cycloalkylalkyl groups can be substituted on the alkyl, cycloalkyl, or on and in the alkyl and cycloalkyl portions of the group. Typical cycloalkylalkyl groups include, but are not limited to, methyl, methylcyclobutyl, methylcyclopentyl, methylcyclohexyl, ethylcyclopropyl, ethylcyclobutyl, ethylcyclopentyl, ethylcyclohexyl, propiltsiklopentil, propylcyclohexyl and the like.

The "aralkyl" group is a radical of the formula -alkyl-aryl, wherein alkyl and aryl are as defined above. Substituted aralkyl groups may be substituted by alkyl on the aryl or the alkyl and aryl parts and groups. Representative aralkyl groups include but are not limited to, benzyl and phenethyl groups and fused (cycloalkylaryl) alkyl groups such as 4-etilindanil.

"Heterocyclylalkyl" group is a radical of the formula -alkyl-heterocyclyl, wherein alkyl and heterocyclyl are defined above. Geterotsiklilalkilnye substituted groups may be substituted by alkyl, heterocyclyl or on and in the alkyl and heterocyclyl portions of the group. Typical heterocyclylalkyl groups include, but are not limited to, 4-ethylmorpholine, 4-propilmorfolinil, furan-2-ylmethyl, furan-3-ylmethyl, pyridin-3-ylmethyl, tetrahydrofuran-2-yl-ethyl, and indol-2-yl-propyl.

"Halogen" represents fluoro, chloro, bromo or iodo.

"Hydroxyalkyl" group is an alkyl group as described above substituted by one or more hydroxy groups.

"Alkoxy" group is an -O- (alkyl) wherein alkyl is as defined above.

"Alkoxyalkyl" is a group - (alkyl) -O- (alkyl) wherein alkyl is as defined above.

"Amino" group is a radical of formula: -NH₂.

"Alkylamino" group is a radical of formula: -NH-alkyl or -N (alkyl)₂Wherein each alkyl is independently defined above.

"Carboxy" group is a radical of formula: -C (O) OH.

"Aminocarbonyl" group is a radical of formula: -C (O) N (R^#)₂, -C(O)NH(R^#) Или -C (O) NH₂Where each R^# independently represents a substituted or unsubstituted alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl or heterocyclyl as defined herein.

"Acylamino" group is a radical of the formula: -NHC (O) (R^#) или -N(алкил)C(O)(R^#) Wherein each alkyl and R^# are independently as defined above.

"Sulfonylamino" group is a radical of the formula: -NHSO₂(R^#) или -N(алкил)SO₂(R^#) Wherein each alkyl and R^# are as defined above.

"Urea" group is a radical of formula: -N (alkyl) C (O) N (R^#)₂, -N(алкил)C(O)NH(R^#), –N(алкил)C(O)NH₂, -NHC(O)N(R^#)₂, -NHC (O) NH (R^#) Или -NH (CO) NHR^#Wherein each alkyl and R^# are independently as defined above.

When the groups described herein, except alkyl groups, indicated as "substituted", that group may be substituted by any suitable substituent or substituents. Typical examples of substituents can be found in the examples of compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; OH; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioester; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfonyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxyl amine; alkoxyamine; aralkoksiamin; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (= O); B (OH)₂, O (alkyl) aminocarbonyl; cycloalkyl which may be monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) or heterocyclyl which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidyl, piperidyl, piperazinyl, morpholinyl or thiazinyl); monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidyl, benzimidazolyl, benzothiophenyl or benzofuranyl) alkyloxy; aralkyloxy; heterocyclyloxy; and geterotsiklilalkoksi.

As used herein, the term "diaminopirimidinovoe compound" refers to compounds of formula (I) and Formula (IB), as well as to other embodiments of the present invention. In one embodiment, the "diaminopirimidinovoe compound" is a compound listed in Tables 1, 2 and 3. The term "diaminopirimidinovoe compound" includes pharmaceutically acceptable salts, tautomers, isotopologues, stereoisomers and prodrugs of the compounds of the present invention.

As used herein, the term "pharmaceutically acceptable (s), salt (s)" refers to a salt prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. Suitable pharmaceutically-acceptable base addition salts of compounds of formula (I) include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N, N'-dibenzylethylenediamine , chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, эtensulyfonovoy, muravyinaya, fumarovaya, furonovaya, galakturonovaya, glyukonovaya, glyukuronovaya, glyumatovaya, glikolinovaya, bromistovodorodnaya, hloristovodorodnaya, izetionovaya, molochnaya, maleinovaya, yablochnaya, maleinovaya, mindalynaya, metansulyfonovaya, mutsinovaya, azotnaya, pamovaya, pantotenovaya, feniluksusnaya, fosfornaya, propionovaya, salitsilovaya, stearinovaya, yantarnaya, sulyfanilovoy, sernaya, vinnaya Chisloth and n-toluolsulyfonovaya Chisloth. Spetsificheskie netoksicheskie kislotы vklyuchayut solyanuyu, bromistovodorodnuyu, maleinovuyu, fosfornuyu, sernuyu and metansulyfonovuyu kislotы. Primerы spetsificheskih Soleil, Takima obrazom, vklyuchayut salts gidrohlorida and mesylate. Others salts horosho izvestnы in dannoy areas cm., For example, Remington's Pharmaceutical Sciences, 18th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19th eds.,

As used herein, unless otherwise indicated, the term "prodrug" denotes diaminopirimidinovoe compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to yield the active compound, in particular diaminopirimidinovogo compound or compounds formula (I). Examples of prodrugs include, but are not limited to, derivatives and metabolites diaminopirimidinovogo compounds that include biohydrolyzable groups such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. In some embodiments, prodrugs of compounds with carboxyl functional groups are the lower alkyl esters of carboxylic acids. Ether carboxylates are typically formed by esterifying any of the carboxylic acid present on the molecule. Prodrugs can typically be prepared using well known methods such as those described Burger's Medicinal Chemistry and Drug Discovery 6^th ed. (Donald J. Abraham ed., 2001, Wiley) и Design и Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers Gmfh).

As used herein, unless otherwise indicated, the term "stereoisomer" or "stereomerically pure" means a compound diaminopirimidinovogo stereoisomer which is substantially free of other stereoisomers of the compound. For example, a stereomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound. Stereomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound. Typically, stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound . greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound. Diaminopirimidinovye compounds may have chiral centers and may occur as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms are included within the scope of the embodiments described herein, including mixtures thereof. individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms are included within the scope of the embodiments described herein, including mixtures thereof. individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms are included within the scope of the embodiments described herein, including mixtures thereof.

Use of stereomerically pure forms of such compounds diaminopirimidinovyh as well as the use of mixtures of those forms are included as embodiments described herein. For example, a mixture containing equivalent or inequivalent amounts of enantiomers of a particular compound diaminopirimidinovogo may be used in the methods and compositions described herein. These isomers may be asymmetrically synthesized or dissolved using standard approaches such as chiral columns or chiral solubilizing agents. .. See, e.g., Jacques, J., et al, Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, SH, et al, Tetrahedron 33: 2725 (1977). Eliel, EL, Stereochemistry of Carbon Compound (McGraw-Hill, NY, 1962); and Wilen, SH,

It should also be noted that diaminopirimidinovye compounds may include E and Z isomers or mixtures thereof, and cis and trans isomers or mixtures thereof. In some embodiments diaminopirimidinovye compound is isolated either in the form of E, or a Z isomer. In other embodiments diaminopirimidinovye compounds represent a mixture of isomers of E and Z.

"Tautomers" refers to isomeric forms of the compounds, which are in equilibrium with each other. The concentrations of the isomeric forms depend on the environment in which the compound is detected, and may vary depending, for example, whether it is a solid compound or is in an organic or aqueous solution. For example, in an aqueous solution, pyrazoles can exist in these isomeric forms which are designated as tautomers of each:

<img file="00000003.jpg" he="17" wi="40" img-format="tif" img-content="undefined" />.

As is well understood by those skilled in the art, a large variety of functional groups and other structures may be tautomerism, and all tautomers of compounds of formula (I) are included within the scope of the present invention.

It should also be noted that the compounds may diaminopirimidinovye contains unnatural proportions of atomic isotopes at one or more atoms. For example, the compounds may be radiolabeled with a radioactive isotope, such as for example tritium (³H), йод-125 (¹²⁵I), сера-35 (³⁵S) or carbon-14 (¹⁴C) or may be isotopically saturated, for example, deuterium (²H),-13 carbon (¹³C) or nitrogen-15 (¹⁵N). As used herein "isotopologue" is an isotopically saturated compound. The term "isotopically saturated" refers to an atom having an isotopic composition other than the natural isotopic kompoztsiii this atom. "Isotopically saturated" can also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom. The term "isotopic composition" refers to the amount of each isotope submitted for a given atom. Labeled isotopically radiolabelled and saturated compounds may be used as therapeutic agents, e.g., anti-cancer and anti-inflammatory therapeutic agents, research tools, e.g., binding assay reagents and as diagnostic agents, e.g., imaging agent in vivo. It is understood that all isotopic variants diaminopirimidinovyh compounds described herein, whether radioactive or not they are within the scope of embodiments of the present invention. In some embodiments, the proposed isotopologues diaminopirimidinovyh compounds, e.g., compounds diaminopirimidinovye isotopologues are saturated with deuterium, carbon-13 or nitrogen-15.

“JNK” обозначает белок или его изоформу, экспрессируемый генами JNK1, JNK2 или JNK3 (Gupta, S., Barrett, T., Whitmarsh, A. J., Cavanagh, J., Sluss, H. K., Derijard, B. and Davis, R. J. The EMBO J. 15:2760-2770 (1996)).

"Treatment" as used herein means an improvement in whole or in part, disorder flow, the disease or condition, or one or more symptoms associated with the disorder, disease or condition, or slowing or arresting the further progression or worsening of those symptoms, or facilitating or eliminating the actual cause (s), disorder, disease or condition. In one embodiment, the disease is a fibrosis of the liver, such as NASH, steatosis (i.e., fatty liver), cirrhosis, primary sclerosing cholangitis, primary biliary cirrhosis, hepatitis, hepatocellular carcinoma or liver fibrosis associated with chronic or recurrent alcohol use ( alcoholic hepatitis), infection (e.g., viral infection, such as HCV), liver transplant or a liver disease caused by the intake of drugs (e.g., atsetaminofenovaya toxicity). In certain embodiments, "treating" means an improvement in whole or in part, disorder flow, the disease or condition or symptoms associated with diabetes or metabolic syndrome, which lead to the development of liver fibrosis, such as NASH, steatosis (i.e., fatty liver), hepatitis or cirrhosis or deceleration, the cessation of further progression or worsening of those symptoms. In one embodiment the symptom is jaundice. In another embodiment, "treatment" means improving, in whole or in part, rastvoroystva, disorder or condition or symptoms associated with a condition,

"Prevention" as used herein denotes a method for delay and / or prevent the onset, propagation retry or fully or partially, disorder, disease or condition; exclusion from the individual the possibility of acquiring the disorder, disease or condition; or reduce the individual risk of acquisition disorders, diseases or conditions. In one embodiment the disease is a fibrosis of the liver, or diabetes or metabolic syndrome, which lead to fibrotic diseases of the liver, as described herein, or symptoms thereof. In another, a disease state is treated or prophylaxis is effective by inhibiting the path JNK.

The term "effective amount" in the context diaminopirimidinovogo compound represents an amount capable for the treatment or prevention of disorders, diseases or conditions or symptoms thereof described herein.

The term "individual" includes an animal, including, but not limited to, an animal such as a cow, monkey, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig, in one of the embodiments - a mammal, in another embodiment, the - human. In one embodiment, the individual is the person with a risk or at risk of developing liver fibrotic diseases or diabetes or metabolic syndrome, which lead to the development of fibrotic liver disease, or condition, the treatment or prevention of which is effective by inhibiting the path JNK, or their symptoms.

Diaminopirimidinovыe soedineniya

As used herein, discloses compounds of the following formula (I):

<img file="00000004.jpg" he="34" wi="35" img-format="tif" img-content="undefined" />

and their pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers and prodrugs isotopologues,

Where:

R¹ represents substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted alkylcycloalkyl, or unsubstituted or substituted alkylheterocyclyl, provided that R¹ It is not 1-aminotsiklogeksilom; and

R² represents substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted saturated cycloalkyl, unsubstituted or substituted alkylcycloalkyl, or substituted or unsubstituted non-aromatic heterocyclyl.

In one embodiment of the present invention, the compound of formula (I) is not:

2- (2-aminoэtilamino) -4- (methylamino) pyrimidine-5-karboksamidom

<img file="00000005.jpg" he="24" wi="48" img-format="tif" img-content="undefined" />,

2- (2-aminopropilamino) 4 (tsiklogyeksilamino) pyrimidic 5 karboksamidom

<img file="00000006.jpg" he="27" wi="48" img-format="tif" img-content="undefined" />,

2- (2-amino-2-oxoethylamino) -4- (ciklogeksilamino) pyrimidine-5-carboxamide

<img file="00000007.jpg" he="26" wi="55" img-format="tif" img-content="undefined" />,

2- (2-aminoethylamino) -4- (ciklogeksilamino) pyrimidine-5-carboxamide

<img file="00000008.jpg" he="23" wi="54" img-format="tif" img-content="undefined" />,

(S) -2- (2-aminopropylamino) -4- (cyclobutylamino) pyrimidine-5-karboksamidom

<img file="00000009.jpg" he="31" wi="45" img-format="tif" img-content="undefined" />,

(R) -2- (1-amino-3-methyl-1-oxobutan-2-ylamino) -4- (cyclobutylamino) pyrimidine-5-karboksamidom

<img file="00000010.jpg" he="32" wi="50" img-format="tif" img-content="undefined" />,

4- (cyclopentylamino) -2- (methylamino) pyrimidine-5-karboksamidom

<img file="00000011.jpg" he="32" wi="34" img-format="tif" img-content="undefined" />,

or 2- (1-acetylpiperidin-4-ylamino) -4- (cyclopropylamino) pyrimidine-5-karboksamidom

<img file="00000012.jpg" he="28" wi="52" img-format="tif" img-content="undefined" />.

In one embodiment of the present invention, R¹ is not

<img file="00000013.jpg" he="16" wi="23" img-format="tif" img-content="undefined" />,

eg,

<img file="00000014.jpg" he="18" wi="98" img-format="tif" img-content="undefined" />

In some embodiments of compounds of formula (I), R¹ It is a branched C_1-8 alkyl, e.g., R¹ is isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylpentyl, or tert-pentyl. In others, R¹ Sobol predstavlяet isopropyl, sec-butyl, isobutyl, tert-butyl, 2,3-dimethylbutyl, isopentyl, 2-methylpentyl, neopentyl, tert-pentyl and 3-methylpentyl. In Others, R¹ It represents a substituted or unsubstituted cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [1.1.1] pentyl, or bicyclo [2.2.2] octyl. In others, cycloalkyl represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [1.1.1] pentyl, bicyclo [2.2.1] heptyl or bicyclo [2.2.2] octyl. In some such embodiments, the cycloalkyl is substituted with one or more halogen, - (C_1-4 alkyl), -NR₂, -(C_0-3 алкил)OR, -NRC(O)R', -C(O)R', -C(O)NR₂, -C(O)OR(или -NRS(O)₂R ', wherein each R independently represents H or C_1-4 alkyl, wherein alkyl is optionally fluorinated, and each R (independently represent a C_1-4 alkyl, wherein alkyl is optionally fluorinated. For example, cycloalkyl substituted with one or more methyl, ethyl, t-butyl, -F, -OH, -OCH₃, -OCHF₂, -OCF₃, -OCH₂CH₃, -OCH₂CH₂F, -OCH₂CF₃, -CH₂OH, -CH₂AND₃, -C(CH₃)₂OH, -NH₂, -NH(CH₃), -NHC (O) CH₃, -C (O) NHCH₃, -WITH CH₃)₂ or -NHSO₂CH₃. In other embodiments, the cycloalkyl is substituted with one or more halogen, -CF₃, -(C_1-4 алкил), -(C_1-6 cycloalkyl), -NR₂, -(C_0-3 алкил)OR, -(C_0-3 алкил)ORʺ, -NRC(O)R', -C(O)R', -C(O)NR₂, -C(O)OR(или -NRS(O)₂R ', wherein each R independently represents H or C_1-4 alkyl, wherein alkyl is optionally fluorinated, each R (independently represent a C_1-4 alkyl, wherein alkyl is optionally fluorinated, and each R "independently represents C_1-6 cycloalkyl wherein the cycloalkyl is optionally fluorinated. For example, cycloalkyl substituted with one or more methyl, ethyl, t-butyl, cyclopropyl, -CF₃, -F, -OH, -OCH₃, -OCHF₂, -OCF₃, -OCH₂CH₃, -OCH₂CH₂F, -OCH₂CF₃, -O (cyclopropyl), -CH₂OH, -CH₂AND₃, -C(CH₃)₂OH, -NH₂, -NH(CH₃), -NHC (O) CH₃, -C (O) NHCH₃, -WITH CH₃)₂ or -NHSO₂CH₃. In some embodiments, R¹ is a substituted or unsubstituted non-aromatic heterocyclyl, for example, pyrrolidinyl, tetrahydropyranyl, 1,4-dioxaspiro [4.5] dekanilom or piperidyl. In other - non-aromatic heterocyclyl is oxetanyl, pyrrolidinyl, tetrahydropyranyl, 1,4-dioxaspiro [4.5] decanyl or piperidyl. In some such embodiments, piperidyl substituted with -C (O) R'ili -C (O) OR ', where R' represents a C_1-4 alkyl, wherein alkyl is optionally fluorinated. In yet another embodiment, R¹ represents substituted or unsubstituted alkylcycloalkyl, e.g., (C_1-3alkyl) cyclopropyl, (C_1-3 alkyl) cyclobutyl, (C_1-3 alkyl), or cyclopentyl (C_1-3 alkyl) cyclohexyl. In some such embodiments, R¹ represents - (CH₂) Cyclopropyl, - (CH₂) Cyclobutyl, - (CH₂) Cyclopentyl, - (CH₂Cyclohexyl, -CH (CH)₃) Cyclopropyl, -CH (CH₃) Cyclobutyl, -CH (CH₃) Cyclopentyl or -CH (CH₃) Cyclohexyl. B - R drwgïx¹ represents - (CH₂) Cyclopropyl, -CH (CH₃) Cyclopropyl, -CH (CH₃) Cyclobutyl, -CH (CH₃Cyclohexyl or -C (CH)₃)₂cyclopropyl. In other embodiments, R¹ represents substituted or unsubstituted alkylheterocyclyl, e.g., - (C_1-4 alkyl) tetrahydrofuranyl, - (C_1-4 алкил)диоксоланил, (C_1-4 alkyl) furanyl, (C_1-3 alkyl) thiophenyl or - (C_1-3 alkyl) pyridyl.

In some embodiments of compounds of formula (I) R¹ is selected from branched C_1-8 alkyl,

<img file="00000015.jpg" he="47" wi="156" img-format="tif" img-content="undefined" />

Where

R^3' It represents halo, -CF₃, -(C_1-4 алкил), -(C_1-6 cycloalkyl), -NR₂, -(C_0-3 алкил)OR, -(C_0-3 алкил)ORʺ, -NRC(O)R', -C(O)R', -C(O)NR₂, -C(O)OR(или -NRS(O)₂R';

R^4' It represents -C (O) R (or -C (O) OR ';

each R independently represents H or C_1-4 alkyl, wherein alkyl optionally fluorinated;

each R 'independently represents a C_1-4 alkyl, wherein alkyl optionally fluorinated;

each R" is independently a C_1-6 cycloalkyl wherein the cycloalkyl is optionally fluorinated; and

n is 0-2.

In some such embodiments, R^3' It represents methyl, ethyl, t-butyl, cyclopropyl, -CF₃, -F, -OH, -OCH₃, -OCHF₂, -OCF₃, -OCH₂CH₃, -OCH₂CH₂F, -OCH₂CF₃, -O (cyclopropyl), -CH₂OH, -CH₂AND₃, -C(CH₃)₂OH, -NH₂, -NH(CH₃), -NHC (O) CH₃, -C (O) NHCH₃, -WITH CH₃)₂ or -NHSO₂CH₃.

In some embodiments, R² represents substituted or unsubstituted C_1-8 alkyl, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, tert-pentyl, isopentyl, or 2-methylpentyl. In other embodiments, R² represents methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 3-methylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 2,3,3-trimethylbutyl, tert-pentyl, isopentyl, 3-pentyl, 3-methylpentyl, 2-methylpentyl or 2,4-dimethylpentyl. In some such embodiments, R² substituted by one or more - (C_1-4 алкил), -(C_0-3 алкил)OR, -C(O)NR₂ or -NRCOR ', wherein each R independently represents H or C_1-4 alkyl, wherein alkyl is optionally fluorinated, and each R 'independently represents a C_1-4 alkyl, wherein alkyl is optionally fluorinated. For example, R² substituted with one or more -OH or -CH₃. In other embodiments, R² substituted with one or more -OH, -OCH₃ или -CH₃. In some embodiments, R² substituted or unsubstituted cycloalkyl, e.g., R² It represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. In some such embodiments, R² substituted by one or more - (C_1-4 алкил), -(C_0-3 алкил)OR, -(C_0-3 алкил)C(O)NR₂, -NR₂ or -NRCOR ', wherein each R independently represents H or C_1-4 alkyl, wherein alkyl is optionally fluorinated, and each R 'independently represents a C_1-4 alkyl, wherein alkyl is optionally fluorinated. In other embodiments, R² predstavlyaet Sobol cyclopropyl, cyclobutyl, cyclopentyl, tsiklogeksil, tsiklogeptil, cyclooctyl, bicyclo [1.1.1] pentyl, bicyclo [2.1.1] Gexto or bicyclo [2.2.1] heptanes. In nekotorыh Taki Alternatively osushtestvleniya, R² substituted with one or more -CF₃, -(C_1-4 алкил), -(C_1-6 cycloalkyl), - (C_0-3 алкил)OR, -(C_0-3 алкил)C(O)NR², -NR² or -NRCOR ', wherein each R independently represents H or C_1-4 alkyl, wherein alkyl is optionally fluorinated, each R 'independently represents a C_1-4 alkyl, wherein alkyl is optionally fluorinated, and wherein the cycloalkyl is optionally fluorinated. In some such embodiments, R² substituted with one or more methyl, ethyl, isopropyl, -CH₂OH, -OH, -OCH₃, -OCH₂CH₃, -C (O) NH₂, -NHC (O) CH₃ или -NHC (O) CH₂CH₃. In other - R² substituted with one or more methyl, ethyl, isopropyl, -tsiklopropilom, -CF₃, -CH₂OH, -OH, -OCH₃, -OCH₂CH₃, -C (O) NH₂, -NHC (O) CH₃ или -NHC (O) CH₂CH₃. In some embodiments, R² It represents substituted or unsubstituted alkylcycloalkyl, e.g., substituted or unsubstituted (C_1-3 alkyl) cyclopropyl, (C_1-3 alkyl) cyclobutyl, (C_1-3 alkyl), or cyclopentyl (C_1-3 alkyl) cyclohexyl. Such as the R² represents - (CH₂) Cyclopropyl, - (CH₂) Cyclobutyl, -CH (CH₃) Cyclopropyl, -CH (CH₃) Cyclobutyl, -CH (CH₂CH₃) Cyclopropyl, -C (CH₃)₂cyclopropyl or -CH₂CH₂cyclobutyl. In some embodiments, R² represents a substituted or unsubstituted non-aromatic heterocyclyl, e.g., tetrahydrofuranyl, tetrahydropyranyl, piperidyl, piperidinone or 1,4-dioxaspiro [4.5] decanyl. In other - R² is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidyl, piperidinone or 1,4-dioxaspiro [4.5] decanyl. In some such embodiments, R² substituted by one or more - (C_1-4 алкил), -(C_0-3 alkyl) OR or -C (O) R ', wherein each R independently represents H or C_1-4 alkyl, wherein alkyl is optionally fluorinated, and each R (independently represent a C_1-4 alkyl, wherein alkyl is optionally fluorinated.

In some embodiments of compounds of formula (I), R² represents substituted or unsubstituted C_1-8 alkyl,

<img file="00000016.jpg" he="45" wi="154" img-format="tif" img-content="undefined" />,

Where

R^5' It is -CF₃, -(C_1-4 алкил), -(C_1-6 cycloalkyl), - (C_0-3 алкил)OR, -(C_0-3 алкил)C(O)NR₂, -NR₂ or -NRCOR ', wherein cycloalkyl is optionally fluorinated;

R^6' It represents H or -C (O) R ';

each R independently represents H or C_1-4 alkyl, wherein alkyl optionally fluorinated;

each R 'independently represents a C_1-4 alkyl, wherein alkyl optionally fluorinated; and

n is 0-2.

In some such embodiments, R^5' It represents methyl, ethyl, isopropyl, cyclopropyl, -CF₃, -CH₂OH, -OH, -OCH₃, -OCH₂CH₃, -C (O) NH₂, -NHC (O) CH₃ или -NHC (O) CH₂CH₃. In some embodiments, R^6' represents H or -C (O) CH₃, -C (O) CH₂CH₃, -C (O) CH (CH₃)₂ или -C(O)CH₂CH (CH₃)₂.

In some such embodiments, R², R¹ It is cycloalkyl optionally substituted with one or more halogens, -CF₃, -(C_1-4 алкил), -(C_1-6 cycloalkyl), -NR₂, -(C_0-3 алкил)OR, -(C_0-3 алкил)ORʺ, -NRC(O)R', -C(O)R', -C(O)NR₂, -C(O)OR(или -NRS(O)₂R ', wherein each R independently represents H or C_1-4 alkyl, wherein alkyl is optionally fluorinated, each R 'independently represents a C_1-4 alkyl, wherein alkyl is optionally fluorinated, and R" each independently represent a C_1-6 cycloalkyl wherein the cycloalkyl is optionally fluorinated.

Other embodiments disclosed herein include a combination of one or more specific embodiments described above.

Representative compounds of formula (I) shown in Table 1.

In some embodiments, the compound is selected from Table 2.

As used herein, discloses compounds of the following formula (IB):

<img file="00000017.jpg" he="29" wi="34" img-format="tif" img-content="undefined" />

and their pharmaceutically acceptable salts, tautomers, stereoisomers, enantiomers and prodrugs isotopologues,

Where:

R³ represents substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted alkylcycloalkyl, or substituted or unsubstituted alkyl (non-aromatic heterocyclyl); and

R⁴ represents substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted non-aromatic heterocyclyl.

In one embodiment, the compound is not

4- (isopentylamino) -2- (3- (2-methylpiperidin-1-yl) propylamino) pyrimidin-5-carbonitrile

<img file="00000018.jpg" he="26" wi="72" img-format="tif" img-content="undefined" />

(2S, 2'S) dimethyl 2,2 '- (5-cyanopyrimidin-2,4-diyl) bis (azanediyl) bis (4-methylpentanoate)

<img file="00000019.jpg" he="33" wi="55" img-format="tif" img-content="undefined" />

(2S, 2'S) diethyl 2,2 '- (5-cyanopyrimidin-2,4-diyl) bis (azanediil) -bis (3-methylbutanoate)

<img file="00000020.jpg" he="38" wi="58" img-format="tif" img-content="undefined" />

4- (cïklogeptïlamïno) -2- (3- (2-methylpiperidine-1-il) propylamino) pyrimidine-5-karbonïtrïlom

<img file="00000021.jpg" he="27" wi="69" img-format="tif" img-content="undefined" />

4- (4-metiltsiklogeksilamino) -2- (3- (2-methylpiperidin-1-yl) propylamino) pyrimidin-5-karbonitrilom

<img file="00000022.jpg" he="27" wi="66" img-format="tif" img-content="undefined" /> or

2- (3- (diethylamino) propylamino) -4- (4-methylcyclohexylamine) -pyrimidine-5-carbonitrile

<img file="00000023.jpg" he="28" wi="69" img-format="tif" img-content="undefined" />

In one embodiment, the compounds of formula (IB), R³ It is a branched C_1-8 alkyl, e.g., R³ is isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylpentyl, or tert-pentyl. In other embodiments, R³ Sobol predstavlяet isopropyl, sec-butyl, isobutyl, tert-butyl, 2,3-dimethylbutyl, isopentyl, 2-methylpentyl, neopentyl, tert-pentyl and 3-methylpentyl. In nekotorыh Alternatively osuщestvleniя R³ It is tert-butyl. In other embodiments, R³ It represents represents a substituted or unsubstituted cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [1.1.1] pentyl, or bicyclo [2.2.2] octyl. In some such embodiments, R³ predstavlyaet Sobol cyclopropyl, cyclobutyl, cyclopentyl, tsiklogeksil, tsiklogeptil, cyclooctyl, bicyclo [1.1.1] pentyl, bicyclo [2.2.1] heptanes or bicyclo [2.2.2] octyl. In nekotorыh Alternatively osushtestvleniya R³ is cyclobutyl or cyclohexyl. In some embodiments, the cycloalkyl is substituted with one or more halogen, -CF₃, -(C_1-4 алкил), -(C_1-6 cycloalkyl), -NR₂, -(C_0-3 алкил)OR, -(C_0-3 алкил)OR”, -NRC(O)R', -C(O)R', -(C_0-3 алкил)C(O)NR₂, -C(O)OR' или -NRS(O)₂R ', wherein each R independently represents H or C_1-4 alkyl, wherein alkyl is optionally fluorinated, and each R 'independently represents a C_1-4 alkyl, wherein alkyl is optionally fluorinated, and each R "independently represents C_1-6 cycloalkyl wherein the cycloalkyl is optionally fluorinated. For example, cycloalkyl substituted with one or more methyl, ethyl, t-butyl, cyclopropyl, -CF₃, -F, -OH, -OCH₃, -OCHF₂, -OCF₃, -OCH₂CH₃, -OCH₂CH₂F, -OCH₂CF₃, -O (cyclopropyl), -CH₂OH, -CH₂AND₃, -C(CH₃)₂OH, -NH₂, -NH(CH₃), -NHC (O) CH₃, -C(CH₃)₂WITH CH₃)₂, -C (O) NHCH₃, -WITH CH₃)₂ or -NHSO₂CH₃. In other embodiments, cycloalkyl substituted with one or more halogen, - (C_1-4 alkyl), -NR₂, -(C_0-3 алкил)OR, -NRC(O)R', -C(O)R', -(C_0-3 алкил)C(O)NR₂, -C(O)OR(или -NRS(O)₂R ', wherein each R independently represents H or C_1-4 alkyl, wherein alkyl is optionally fluorinated, and each R (independently represent a C_1-4 alkyl, wherein alkyl is optionally fluorinated. For example, cycloalkyl substituted with one or more methyl, ethyl, t-butyl, -F, -OH, -OCH₃, -OCHF₂, -OCF₃, -OCH₂CH₃, -OCH₂CH₂F, -OCH₂CF₃, -O (cyclopropyl), -CH₂OH, -CH₂AND₃, -C(CH₃)₂OH, -NH₂, -NH(CH₃), -NHC (O) CH₃, -C(CH₃)₂WITH CH₃)₂, -C (O) NHCH₃, -WITH CH₃)₂ or -NHSO₂CH₃. In some embodiments, the cycloalkyl is substituted with one or more methyl, -F, -OH, -OCH₃, -OCH₂CH₃, -OCHF₂, -OCH₂CF₃, -NH(CH₃), -NHC (O) CH₃, -WITH CH₃)₂ или -C(CH₃)₂WITH CH₃)₂. In other embodiments, R³ It represents a substituted or unsubstituted non-aromatic heterocyclyl, e.g., pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,4-dioxaspiro [4.5] decanyl or piperidyl. In some embodiments, non-aromatic heterocyclyl is oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidyl, piperidinone or 1,4-dioxaspiro [4.5] decanyl. In some embodiments, R³ It represents tetrahydropyranyl. In some embodiments, piperidyl substituted with -C (O) R (or -C (O) OR ', wherein R (is a C_1-4 alkyl, wherein alkyl is optionally fluorinated. In some embodiments, R³ It represents represents a substituted or unsubstituted alkylcycloalkyl, e.g., (C_1-3 alkyl) cyclopropyl, (C_1-3 alkyl) cyclobutyl, (C_1-3 alkyl), or cyclopentyl (C_1-3 alkyl) cyclohexyl. In some embodiments, R³ represents - (CH₂) Cyclopropyl, - (CH₂) Cyclobutyl, - (CH₂) Cyclopentyl, - (CH₂Cyclohexyl, -CH (CH)₃) Cyclopropyl, -CH (CH₃) Cyclobutyl, -CH (CH₃) Cyclopentyl or -CH (CH₃) Cyclohexyl. Drwgïx, R³ represents - (CH₂) Cyclopropyl, -CH (CH₃) Cyclopropyl, -CH (CH₃) Cyclobutyl, -CH (CH₃Cyclohexyl or -C (CH)₃)₂cyclopropyl. In some embodiments, R³ represents substituted or unsubstituted alkyl (non-aromatic heterocyclic), e.g., - (C_1-4 alkyl) tetrahydrofuranyl or - (C_1-4 alkyl) dioxolanyl.

In some embodiments of compounds of formula (IB) R³ is selected from branched C_1-8 alkyl,

<img file="00000024.jpg" he="33" wi="110" img-format="tif" img-content="undefined" />

Where

R^3' predstavyaet halogen, -CF₃, -(C_1-4 алкил), -(C_1-6 cycloalkyl), -NR₂, -(C_0-3 алкил)OR, -(C_0-3 алкил)ORʺ, -NRC(O)R', -C(O)R', -C(O)NR₂, -C(O)OR(или -NRS(O)₂R';

R^4' It represents -C (O) R (or -C (O) OR ';

each R independently represents H or C_1-4 alkyl, wherein alkyl optionally fluorinated;

each R 'independently represents a C_1-4 alkyl, wherein alkyl optionally fluorinated;

each R" is independently a C_1-6 cycloalkyl wherein the cycloalkyl is optionally fluorinated; and

n is 0-2.

In some embodiments, R^3' predstavyaet is methyl, ethyl, t-butyl, cyclopropyl, -CF₃, -F, -OH, -OCH₃, -OCHF₂, -OCF₃, -OCH₂CH₃, -OCH₂CH₂F, -OCH₂CF₃, -O (cyclopropyl), -CH₂OH, -CH₂AND₃, -C(CH₃)₂OH, -NH₂, -NH(CH₃), -NHC (O) CH₃, -C (O) NHCH₃, -WITH CH₃)₂ or -NHSO₂CH₃.

In some embodiments of compounds of formula (IB), R³ is selected from branched C_1-8 alkyl,

<img file="00000025.jpg" he="18" wi="154" img-format="tif" img-content="undefined" />

Where

R^3' represents halogen, - (C_1-4 alkyl), -NR₂, -(C_0-3 алкил)OR, -NRC(O)R', -C(O)R', -(C_0-3 алкил)C(O)NR₂, -C(O)OR(или -NRS(O)₂R';

each R independently represents H or C_1-4 alkyl, wherein alkyl is optionally fluorinated, each R (independently represent a C_1-4 alkyl, wherein alkyl optionally fluorinated; and

n is 0-2.

In some such embodiments, R^3' predstavyaet is methyl, ethyl, t-butyl, -F, -OH, -OCH₃, -OCHF₂, -OCF₃, -OCH₂CH₃, -OCH₂CH₂F, -OCH₂CF₃, -CH₂OH, -CH₂AND₃, -C(CH₃)₂OH, -NH₂, -NH(CH₃), -NHC (O) CH₃, -C(CH₃)₂WITH CH₃)₂, -C (O) NHCH₃, -WITH CH₃)₂ or -NHSO₂CH_3.

In some embodiments of compounds of formula (IB), R⁴ represents substituted or unsubstituted C_1-8 alkyl, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylpentyl, or tert-pentyl. In some embodiments, R⁴ represents methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 3-methylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 2,3,3-trimethylbutyl, tert-pentyl, isopentyl, 3-pentyl, 3-methylpentyl, 2-methylpentyl or 2,4-dimethylpentyl. In some embodiments, R⁴ It represents isopropyl, isobutyl, isopentyl, tert-butyl or tert-pentyl. In some such embodiments, R⁴ substituted by one or more - (C_1-4 алкил), -(C_0-3 алкил)OR, -C(O)NR₂ or -NRCOR ', wherein each R independently represents H or C_1-4 alkyl, wherein alkyl is optionally fluorinated, and each R 'independently represents a C_1-4 alkyl, wherein alkyl is optionally fluorinated. For example, R⁴ substituted with one or more -OH or -CH₃. In certain other embodiments, R⁴ It represents a substituted or unsubstituted cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [1.1.1] pentyl, bicyclo [2.1.1] hexyl or bicyclo [2.2.1] heptyl. In some embodiments, R⁴ It represents cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo [1.1.1] pentyl. In some embodiments, R⁴ substituted with one or more halogen, -CF₃, -(C_1-4 алкил), -(C_1-6 cycloalkyl), - (C_0-3 алкил)OR, -(C_0-3 алкил)C(O)NR₂, -NR₂ or -NRCOR ', wherein each R independently represents H or C_1-4 alkyl, wherein alkyl is optionally fluorinated, each R 'independently represents a C_1-4 alkyl, wherein alkyl is optionally fluorinated, and wherein the cycloalkyl is optionally fluorinated. For example, R⁴ substituted with one or more methyl, ethyl, isopropyl, -tsiklopropilom, -CF₃, -CH₂OH, -OH, -OCH₃, -OCH₂CH₃, -C (O) NH₂, -NHC (O) CH₃ или -NHC (O) CH₂CH₃. In some embodiments, R⁴ substituted with one or more halogen, - (C_1-4 алкил), -(C_0-3 алкил)OR, -(C_0-3 алкил)C(O)NR₂, -NR₂ or -NRCOR ', wherein each R independently represents H or C_1-4 alkyl, wherein alkyl is optionally fluorinated, and each R (independently represent a C_1-4 alkyl, wherein alkyl is optionally fluorinated. In some such embodiments, R⁴ substituted with one or more F, methyl, ethyl, isopropyl, -CH₂OH, -OH, -OCH₃, -OCH₂CH₃, -OCHF₂, -OCH₂CF₃, -C (O) NH₂, -C (O) NHCH₃, -WITH CH₃)₂, -CH₂C (O) NH₂, -CH₂C (O) NHCH₃, -CH₂WITH CH₃)₂, -CH (CH₃) C (O) NH₂, -CH (CH₃) C (O) NHCH₃, -CH (CH₃)WITH CH₃)₂, -C(CH₃)₂C (O) NH₂, -C(CH₃)₂C (O) NHCH₃, -C(CH₃)₂WITH CH₃)₂, -NH(CH₃), -NHC (O) CH₃ или -NHC (O) CH₂CH₃. In some embodiments, R⁴ substituted with one or more methyl, ethyl, -F, -CH₂OH or -OH. In some embodiments, R⁴ It represents a substituted or unsubstituted non-aromatic heterocyclyl, for example oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidyl, piperidinone or 1,4-dioxaspiro [4.5] decanyl. In some embodiments, R⁴ is tetrahydrofuranyl or tetrahydropyranyl. In some such embodiments, R⁴ substituted by one or more - (C_1-4 алкил), -(C_0-3 alkyl) OR or -C (O) R ', wherein each R independently represents H or C_1-4 alkyl, wherein alkyl is optionally fluorinated, and each R 'independently represents a C_1-4 alkyl, wherein alkyl is optionally fluorinated.

In some embodiments of compounds of formula (IB), R⁴ represents substituted or unsubstituted C_1-8 alkyl,

<img file="00000026.jpg" he="38" wi="113" img-format="tif" img-content="undefined" />

Where

R^5' It is -CF₃, -(C_1-4 алкил), -(C_1-6 cycloalkyl), - (C_0-3 алкил)OR, -(C_0-3 алкил)C(O)NR₂, -NR₂ or -NRCOR ', wherein cycloalkyl is optionally fluorinated;

R^6' It represents H or -C (O) R ';

each R independently represents H or C_1-4 alkyl, wherein alkyl optionally fluorinated;

each R 'independently represents a C_1-4 alkyl, wherein alkyl optionally fluorinated; and

n is 0-2.

In some such embodiments, R⁵(Predstvlyayu is methyl, ethyl, isopropyl, cyclopropyl, -CF₃, -CH₂OH, -OH, -OCH₃, -OCH₂CH₃, -C (O) NH₂, -NHC (O) CH₃ или -NHC (O) CH₂CH₃. In some embodiments, R^6' represents H or -C (O) CH₃, -C (O) CH₂CH₃, -C (O) CH (CH₃)₂ или -C(O)CH₂CH (CH₃)₂.

In some embodiments of compounds of formula (IB) R⁴ represents substituted or unsubstituted C_1-8 alkyl,

<img file="00000027.jpg" he="44" wi="87" img-format="tif" img-content="undefined" />

Where

R^5' represents halogen, - (C_1-4 алкил), -(C_0-3 алкил)OR, -(C_0-3 алкил)C(O)NR₂, -NR₂ or -NRCOR ';

each R independently represents H or C_1-4 alkyl, wherein alkyl optionally fluorinated;

each R 'independently represents a C_1-4 alkyl, wherein alkyl optionally fluorinated;

and

n is 0-2.

In some such embodiments, R^5' is F, methyl, ethyl, isopropyl, -CH₂OH, -OH, -OCH₃, -OCH₂CH₃, -OCHF₂, -OCH₂CF₃, -C (O) NH₂, -C (O) NHCH₃, -WITH CH₃)₂, -CH₂C (O) NH₂, -CH₂C (O) NHCH₃, -CH₂WITH CH₃)₂, -CH (CH₃) C (O) NH₂, -CH (CH₃) C (O) NHCH₃, -CH (CH₃)WITH CH₃)₂, -C(CH₃)₂C (O) NH₂, -C(CH₃)₂C (O) NHCH₃, -C(CH₃)₂WITH CH₃)₂, -NH(CH₃), -NHC (O) CH₃ или -NHC (O) CH₂CH₃. In some embodiments, R^5' It is F, -OH, -OCH₃, -OCH₂CH₃, -OCHF₂, -OCH₂CF₃, -NH(CH₃), -NHC (O) CH₃, -WITH CH₃)₂, -C(CH₃)₂WITH CH₃)₂.

In some embodiments where R⁴ It represents a substituted or unsubstituted cycloalkyl, R³ It is cycloalkyl optionally substituted with one or more halogen, -CF₃, -(C_1-4 алкил), -(C_1-6 cycloalkyl), -NR₂, -(C_0-3 алкил)OR, -(C_0-3 алкил)ORʺ, -NRC(O)R', -C(O)R', -C(O)NR₂, -C(O)OR' или -NRS(O)₂R ', wherein each R independently represents H or C_1-4 alkyl, wherein alkyl is optionally fluorinated, each R 'independently represents a C_1-4 alkyl, wherein alkyl is optionally fluorinated and each R "independently represents C_1-6 cycloalkyl wherein the cycloalkyl is optionally fluorinated.

Other embodiments include combinations of one or more specific embodiments described above.

Representative compounds of Formula (IB) are listed in Table 3.

Diaminopirimidinovye compounds listed in Table 1, Table 2 and Table 3 were assayed in the inhibition of JNK assays, described herein and shown that they possess the activity of JNK inhibitors. In one embodiment, the compound is a diaminopyrimidine compound described herein, wherein the compound with a concentration of 10 uM inigibiruet JNK1 at least about 50% or more.

Methods for preparing compounds diaminopirimidinovyh

Diaminopirimidinovye compounds can be obtained using conventional organic synthesis methods and commercially available starting materials. By way of example, and not limitation, diaminopirimidinovye compound of formula (I) can be prepared as shown in Schemes 1-9 below and in the examples herein. It should be noted that those skilled in the art will understand how to modify the methods shown in the illustrative schemes and examples to obtain the desired products.

scheme 1

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As shown in Scheme 1, formula (I) compounds wherein R¹ and R² as defined herein, may be prepared starting with an appropriately modified 4-chloro-2-alkiltiopirimidinkarboksilata (wherein each R^x independently represents C_1-2 alkyl) by treatment with R²NH₂ at elevated temperature (e.g., 60-80 ° C) in an organic solvent (e.g., ethanol, methanol, isopropanol, THF, NMP, DMF, DMSO, or dioxane) in the presence of a base (e.g., DIEA, TEA, N-methylmorpholine, 1,8-diazabicyclo [5.4.0] undec-7-ene, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate or potassium phosphate). Hydrolysis of the ester was achieved by treatment with aqueous base, such as, e.g., aqueous sodium hydroxide, potassium hydroxide or lithium hydroxide, in a cosolvent, such as ethanol, methanol, isopropanol, THF, or dioxane. Education amine accompanied by reaction with NH₄Cl in the presence and the binder agent (such as, for example, HATU, CDI, HBTU, EDC , optionally in combination with HOBt or ethyl chloroformate) in an organic solvent such as NMP, DMF, DMSO, dioxane, THF, DCM or chloroform, in the presence of a base (such as DIEA, TEA or potassium carbonate). Oxidation of alkylthio group is achieved by treatment in an organic solvent (such as, e.g., acetone, DCM, NMP, DMF or chloroform), an oxidant such as mCPBA, oxone, hydrogen peroxide or 3-phenyl-2- (phenylsulfonyl) -1,2 oxaziridine. The resulting mixture of the sulfone (m = 1) and the sulfoxide (m = 2) treated at an elevated temperature (e.g., 80-100 ° C) R¹NH₂ in a solvent (such as, e.g., dioxane, DMSO, NMP, DMF, THF, or water) in the presence of an organic base such as DIEA, TEA, N-methylmorpholine or 1,8-diazabicyclo [5.4.0] undec-7-ene to give compounds of formula (I).

scheme 2

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Alternatively, compounds of formula (I) can be prepared as shown in Scheme 2 (wherein R¹, R² and R^x are as defined above). Processing alkyl 2,4-dichloropyrimidine-5-carboxylate using NaSR^x in an organic solvent (e.g., THF, DCM or dioxane) in the presence of a catalyst (e.g., trietilbenzilhlorida ammonium tetrabutilhlorida ammonium or tetrabutyl ammonium bromide) under cooling (e.g., -10 ° C) yielded a mixture tioalkilovyh derivatives. Postprocessing R¹NH₂ at elevated temperature (e.g. 80 ° C) in an organic solvent (e.g., dioxane, THF, NMP, DMF, DMSO, ethanol, methanol or isopropanol) in the presence of a base (e.g., DIEA, TEA, N-methylmorpholine, 1.8 -diazabitsiklo [5.4.0] undec-7-ene, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate or potassium phosphate) introduced a side chain R¹. Hydrolysis of the alkyl ester binding to NH₄Cl and oxidation, as described above, gave a mixture of sulfone (m = 1) and the sulfoxide (m = 2) derivatives which are treated with R²NH₂ in a solvent (such as dioxane, NMP, DMF, DMSO, THF, or water) in the presence of an organic base (such as DIEA, TEA, 1,8-diazabicyclo [5.4.0] undec-7-ene or N-methylmorpholine), at elevated temperature (e.g., 80-110 ° C), giving the compound of formula (I).

scheme 3

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Compounds of formula (I) may also be prepared as shown in Scheme 3. Treatment of an alkyl 2,4-dichloropyrimidine-5-carboxylate using R²NH₂ in a solvent (e.g., ethyl ether, THF, DCM, toluene or methyl tert-butyl ether) in the presence of a base (e.g., DIEA, TEA, 1,8-diazabicyclo [5.4.0] undec-7-ene, N-methylmorpholine, sodium bicarbonate, cesium carbonate or potassium phosphate) at low temperature (e.g., -70 ° C) provided the introduction of the side chain R². Separation of the mixture of regioisomers and hydrogenation of chlorine remaining in the sample provides regiomernoe introduction of the side chain R². The title compound was then regioisomeric further processing modifitsiruyut.Posleduyuschaya R¹NH₂ in an organic solvent (e.g., THF, NMP, DMF, DMSO, dioxane, ethanol, methanol or isopropanol) in the presence of a base (e.g., DIEA, TEA, 1,8-diazabicyclo [5.4.0] undec-7-ene, N- methylmorpholine, sodium carbonate, sodium bicarbonate, cesium carbonate or potassium phosphate) at elevated temperature (e.g. 70 ° C) allows introduction of the side chain R¹. Hydrolysis of the alkyl ester and coupling with NH₄Cl, as described above, yields compounds of formula (I).

scheme 4

<img file="00000031.jpg" he="39" wi="143" img-format="tif" img-content="undefined" />

Scheme 4 shows an alternative method for the synthesis of compounds of formula (I). Treatment of 2,4-dichloropyrimidine-5-carbonitrile using R²NH₂ in an organic solvent (e.g., ethanol, methanol, isopropanol or THF) in the presence of a base (e.g., DIEA, TEA, 1,8-diazabicyclo [5.4.0] undec-7-ene, N-methylmorpholine, sodium carbonate, sodium bicarbonate, cesium carbonate or potassium phosphate) at low temperature (e.g., -60 ° C) provided the introduction of the side chain R². As stated above, the hydrogenation of the remaining chlorine provided the regioisomeric introduction R². Postprocessing R¹NH₂ in an organic solvent (e.g., 1-butanol, THF, NMP, DMF, DMSO, dioxane, ethanol, methanol or isopropanol) in the presence of a base (e.g., cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate, 1.8 -diazabitsiklo [5.4.0] undec-7-ene, N-methylmorpholine, TEA or DIEA) at elevated temperature (e.g. 120 ° C) provides an introduction Bokoy chain R¹ (Yield, in some cases, if R¹=R³ and R²=R⁴, Compounds of formula (IB)). Conversion of the nitrile group using for example, catalytic peroxide in the presence of an aqueous solution of a strong base such as sodium hydroxide or potassium hydroxide, in a solvent such as, for example, DMSO, NMP, DMF, ethanol or methanol to afford compounds of formula (I) .

scheme 5

<img file="00000032.jpg" he="23" wi="160" img-format="tif" img-content="undefined" />

Scheme 5 illustrates another method for synthesizing compounds of formula (I). Treatment of 4-chloro-2- (alkylthio) pyrimidin-5-carbonitrile using R¹NH₂ in an organic solvent (e.g., n-butanol, NMP, DMF, DMSO, dioxane or ethanol) in the presence of a base (such as, for example, DIEA, TEA, N-methylmorpholine, 1,8-diazabicyclo [5.4.0] undec-7 -ene, potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate or potassium phosphate) at a temperature between 50 ° C and 90 ° C) provided the introduction of the side chain R¹. Carbonitrile Conversion to amide, for example, by treatment with peroxide (H₂O₂) In a solvent (such as, e.g., DMSO, NMP, DMF, ethanol or methanol) in the presence of a base (such as sodium hydroxide or potassium hydroxide) and oxidation (for example using mCPBA, oxone, hydrogen peroxide or 3-phenyl -2- (phenylsulfonyl) -1,2-oxaziridine, in a solvent such as DCM, NMP, DMF or DMA), gave a mixture of the sulfone (m = 1) and the sulfoxide (m = 2) as defined above, which may be treated with R²NH₂ in a solvent such as a (dioxane, DMSO, NMP, DMF, THF or n-butanol) in the presence of a base (such as DIEA, TEA, 1,8-diazabicyclo [5.4.0] undec-7-ene or N-methylmorpholine) optionally, at elevated temperature (e.g., in the range room temperature to 130 ° C) to obtain compounds of formula (I).

scheme 6

<img file="00000033.jpg" he="76" wi="143" img-format="tif" img-content="undefined" />

Compounds of formula (I) can be prepared as shown in Scheme 6. Treatment of 5-bromo-2-chloro-4- (alkylthio) pyrimidine via R¹NH₂ in an organic solvent (e.g., n-butanol, NMP, DMF, DMSO, dioxane or ethanol) in the presence of a base (such as, for example, DIEA, TEA, N-methylmorpholine, 1,8-diazabicyclo [5.4.0] undets- 7-ene, potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate or potassium phosphate) at a temperature between 80 ° C and 100 ° C, provided the introduction of the side chain R¹. Introduction carbonitrile group was achieved by treatment with zinc and ditsianotsinkom in a solvent (such as DMF, DMSO, NMP or DMA) in the presence of a catalyst such as Pd (O), at an elevated temperature (e.g. between 80 ° C-100 ° C). As indicated above, conversion of the amide group by treatment with peroxide and then oxidation to the sulfone / sulfoxide, and treatment of R²NH₂ afforded the formula (I) compound. Alternatively, an alkylthio first oxidized, and then introduced into a side chain R²(Yield, in some cases, if R¹=R³ and R²=R⁴ a compound of formula (IB)), and conversion to the amide group to give compound of formula (I).

Alternatively, diaminopirimidinovye compound of formula (IB), wherein R³ and R⁴ as defined herein, may be prepared as shown in Schemes 7, 8 and 9 as shown below and in the examples herein. It should be noted that those skilled in the art will understand how to modify the methods shown in the illustrative schemes and examples to obtain the desired products.

scheme 7

<img file="00000034.jpg" he="43" wi="116" img-format="tif" img-content="undefined" />

As shown in Scheme 7, treatment of 2,4-dichloro-5-carbonitrile using R⁴NH₂ in an organic solvent (e.g., ethanol, methanol, isopropanol or THF) in the presence of a base (e.g., DIEA, TEA, 1,8-diazabicyclo [5.4.0] undec-7-ene, N-methylmorpholine, sodium carbonate, sodium bicarbonate, cesium carbonate or potassium phosphate) provided the introduction of the side chain R⁴. Postprocessing R³NH₂ in an organic solvent (e.g., 1-butanol, THF, NMP, DMF, DMSO, dioxane, ethanol, methanol or isopropanol) in the presence of a base (e.g., cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate, 1.8 -diazabitsiklo [5.4.0] undec-7-ene, N-methylmorpholine, TEA or DIEA) at elevated temperature (e.g. 50 ° C-90 ° C) gave the compound of formula (IB).

scheme 8

<img file="00000035.jpg" he="36" wi="98" img-format="tif" img-content="undefined" />

Alternatively, the substituent R³ is introduced first, and then introduced substituent R⁴ substantially the same procedures as shown in Scheme 8. In some embodiments, binding to R⁴NH₂ carried out at a temperature between room temperature and 110 ° C.

Figure 9

<img file="00000036.jpg" he="23" wi="153" img-format="tif" img-content="undefined" />

In a third embodiment of the method the compound of formula (IB) may be prepared starting with an appropriately modified 4-chloro-2-alkiltiopirimidinkarbonitrila (wherein each R^x independently represents C_1-2 alkyl) by treatment with R⁴NH₂ at elevated temperature (e.g. 50 ° C-90 ° C) in an organic solvent (e.g., n-butanol, NMP, DMF, DMSO, or dioxane) in the presence of a base (e.g., DIEA, TEA, N-methylmorpholine, 1.8 -diazabitsiklo [5.4.0] undec-7-ene, potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate or potassium phosphate). Oxidation of alkylthio group carried out by treatment in an organic solvent (such as, for example, DCM, NMP, DMF or DMA) an oxidizing reagent such as mCPBA, oxone, hydrogen peroxide or 3-phenyl-2- (phenylsulfonyl) -1,2-oxaziridine. The resulting mixture of the sulfone (m = 1) and the sulfoxide (m = 2) was treated at room temperature or elevated temperature (e.g. 25 ° C-110 ° C) via R³NH₂ in a solvent (such as, e.g., dioxane, DMSO, NMP, DMF, THF or n-butanol) in the presence of an organic base such as DIEA, TEA, 1,8-diazabicyclo [5.4.0] undec-7-ene, N -methylmorpholine, to obtain the compounds of formula (IB).

In one aspect, methods are provided for preparing a compound of formula (I):

<img file="00000037.jpg" he="34" wi="38" img-format="tif" img-content="undefined" />

methods include contacting a compound of formula (Ia)

<img file="00000038.jpg" he="34" wi="40" img-format="tif" img-content="undefined" />

c R¹NH₂ in a solvent in the presence of an organic base,

Where:

R¹ represents substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted alkylcycloalkyl, or unsubstituted or substituted alkylheterocyclyl, provided that R¹ It is not 1-aminotsiklogeksilom;

R² represents substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted saturated cycloalkyl, unsubstituted or substituted alkylcycloalkyl, unsubstituted or substituted non-aromatic heterocyclyl;

R^x It represents C_1-2 alkyl; and

m is 1 or 2.

In one embodiment, the compound of formula (I) is not 2- (2-aminoethylamino) -4- (methylamino) pyrimidine-5-carboxamide; 2- (2-aminopropylamino) -4- (cyclohexylamino) pyrimidine-5-carboxamide; 2- (2-amino-2-oxo-ethylamino) -4- (cyclohexylamino) pyrimidine-5-carboxamide; 2- (2-aminoethylamino) -4- (cyclohexylamino) pyrimidine-5-carboxamide; (S) -2- (2-aminopropylamino) -4- (cyclobutylamino) pyrimidine-5-carboxamide; (R) -2- (1-amino-3-methyl-1-oxobutan-2-ylamino) -4- (cyclobutylamino) pyrimidine-5-carboxamide; 4- (cyclopentylamino) -2- (methylamino) pyrimidine-5-carboxamide; or 2- (1-acetylpiperidin-4-ylamino) -4- (cyclopropylamino) pyrimidine-5-carboxamide.

In one embodiment the solvent is dioxane, DMSO, NMP, DMF, THF or water. In another base is DIEA, TEA, 1,8-diazabicyclo [5.4.0] undec-7-ene or N-methylmorpholine. In some embodiments, contacting is carried out at elevated temperature, e.g., about 80 ° C to about 100 ° C.

In some embodiments, the methods further comprise preparing a compound of formula (Ia):

<img file="00000039.jpg" he="35" wi="39" img-format="tif" img-content="undefined" />

oxidation methods include compounds of formula (Ib)

<img file="00000040.jpg" he="33" wi="32" img-format="tif" img-content="undefined" />

in a solvent by treatment with an oxidizing agent selected from mCPBA, Oxone, hydrogen peroxide or 3-phenyl-2- (phenylsulfonyl) -1,2-oxaziridine.

In one embodiment the solvent is acetone, DCM, NMP, DMF or chloroform. In some embodiments, the method is carried out at a temperature between about 0 ° C and about 20 ° C.

In some embodiments, the methods further comprise preparing a compound of formula (Ib):

<img file="00000041.jpg" he="35" wi="32" img-format="tif" img-content="undefined" />

methods include contacting a compound of formula (Ic)

<img file="00000042.jpg" he="33" wi="32" img-format="tif" img-content="undefined" />

с NH₄Cl in the presence of a coupling agent and a base in a solvent.

In some embodiments, the solvent is NMP, DMF, DMSO, dioxane, THF, DCM or chloroform. In other - the binding agent is HATU, CDI, HBTU, EDC / HOBt or ethyl chloroformate, and the base is DIEA, TEA or potassium carbonate.

In some embodiments, the methods further comprise preparing a compound of formula (Ic)

<img file="00000043.jpg" he="34" wi="30" img-format="tif" img-content="undefined" />

methods include contacting a compound of formula (Id)

<img file="00000044.jpg" he="33" wi="36" img-format="tif" img-content="undefined" />

with an aqueous base solution in a cosolvent.

In some embodiments, the aqueous base solution is an aqueous solution of sodium hydroxide, potassium hydroxide or lithium hydroxide. In other embodiments, the cosolvent is ethanol, methanol, isopropanol, THF, or dioxane.

In some embodiments, the methods further comprise preparing a compound of formula (Id)

<img file="00000045.jpg" he="33" wi="34" img-format="tif" img-content="undefined" />

methods include contacting a compound of formula (Ie)

<img file="00000046.jpg" he="33" wi="38" img-format="tif" img-content="undefined" />

with R²NH₂ in an organic solvent in the presence of a base.

In some embodiments, the organic solvent is ethanol, methanol, isopropanol, THF, NMP, DMF, DMSO, or dioxane. In other - the base is DIEA, TEA, N-methylmorpholine, 1,8-diazabicyclo [5.4.0] undec-7-ene, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate or potassium phosphate. In some embodiments, contacting is carried out at elevated temperature, e.g., about 60 ° C to about 80 ° C.

In some embodiments, the methods further comprise preparing a compound of formula (Ib)

<img file="00000047.jpg" he="32" wi="30" img-format="tif" img-content="undefined" />

methods include contacting a compound of formula (If)

<img file="00000048.jpg" he="31" wi="33" img-format="tif" img-content="undefined" />

with a peroxide in the presence of a base in a solvent.

In some embodiments, the solvent is DMSO, NMP, DMF, ethanol or methanol. In other - the base is sodium hydroxide or potassium hydroxide.

In some embodiments, the methods further comprise preparing a compound of formula (If)

<img file="00000049.jpg" he="32" wi="31" img-format="tif" img-content="undefined" />

methods include contacting a compound of formula (Ig)

<img file="00000050.jpg" he="30" wi="31" img-format="tif" img-content="undefined" />

with R²NH₂ in an organic solvent in the presence of a base.

In some embodiments, the organic solvent is n-butanol, NMP, DMF, DMSO, dioxane or ethanol. In other - the base is DIEA, TEA, N-methylmorpholine, 1,8-diazabicyclo [5.4.0] undec-7-ene, potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate or potassium phosphate. In some embodiments, contacting is carried out at elevated temperature, e.g., about 50 ° C to about 90 ° C.

In addition, methods are provided for preparing a compound of formula (I):

<img file="00000051.jpg" he="33" wi="37" img-format="tif" img-content="undefined" />

methods include contacting a compound of formula (IIa)

<img file="00000052.jpg" he="29" wi="40" img-format="tif" img-content="undefined" />

(IIa),

with R²NH₂ in a solvent in the presence of an organic base,

Where:

R¹ represents substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted alkylcycloalkyl or unsubstituted or substituted alkylheterocyclyl, provided that R¹ It is not 1-aminotsiklogeksilom;

R² represents substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted saturated cycloalkyl, unsubstituted or substituted alkylcycloalkyl, unsubstituted or substituted non-aromatic heterocyclyl;

R^x It represents C_1-2 alkyl; and

m is 1 or 2.

In one embodiment of the present invention, the compound of formula (I) is not 2- (2-aminoethylamino) -4- (methylamino) pyrimidine-5-carboxamide; 2- (2-aminopropylamino) -4- (cyclohexylamino) pyrimidine-5-carboxamide; 2- (2-amino-2-oxo-ethylamino) -4- (cyclohexylamino) pyrimidine-5-carboxamide; 2- (2-aminoethylamino) -4- (cyclohexylamino) pyrimidine-5-carboxamide; (S) -2- (2-aminopropylamino) -4- (cyclobutylamino) pyrimidine-5-carboxamide; (R) -2- (1-amino-3-methyl-1-oxobutan-2-ylamino) -4- (cyclobutylamino) pyrimidine-5-carboxamide; 4- (cyclopentylamino) -2- (methylamino) pyrimidine-5-carboxamide; or 2- (1-acetylpiperidin-4-ylamino) -4- (cyclopropylamino) pyrimidine-5-carboxamide.

In one embodiment the solvent is dioxane, DMSO, NMP, DMF, THF or water. In another - the base is DIEA, TEA, 1,8-diazabicyclo [5.4.0] undec-7-ene or N-methylmorpholine. In some embodiments, contacting is carried out at elevated temperature, e.g., about 80 ° C to about 110 ° C.

In some embodiments, the methods further comprise preparing a compound of formula (IIa):

<img file="00000053.jpg" he="27" wi="35" img-format="tif" img-content="undefined" />

(IIa),

methods comprising the oxidation of a compound of formula (IIb)

<img file="00000054.jpg" he="33" wi="37" img-format="tif" img-content="undefined" />

in a solvent by treatment with an oxidizing agent selected from mCPBA, Oxone, hydrogen peroxide or 3-phenyl-2- (phenylsulfonyl) -1,2-oxaziridine.

In one embodiment the solvent is acetone, DCM, NMP, DMF or chloroform. In some embodiments, oxidation is carried out at a low temperature, for example at about 0 ° C.

In some embodiments, the methods further comprise preparing a compound of formula (IIb):

<img file="00000055.jpg" he="34" wi="35" img-format="tif" img-content="undefined" />

methods include contacting a compound of formula (IIc)

<img file="00000056.jpg" he="33" wi="37" img-format="tif" img-content="undefined" />

с NH₄Cl in the presence of a coupling agent and a base in a solvent.

In some embodiments, the solvent is NMP, DMF, DMSO, dioxane, THF, DCM or chloroform. In other - the binding agent is HATU, CDI, HBTU, EDC / HOBt or ethyl chloroformate, and the base is DIEA, TEA or potassium carbonate.

In some embodiments, the methods further comprise preparing a compound of formula (IIc)

<img file="00000057.jpg" he="33" wi="35" img-format="tif" img-content="undefined" />

methods include contacting a compound of formula (IId)

<img file="00000058.jpg" he="33" wi="37" img-format="tif" img-content="undefined" />

with aqueous base, in a cosolvent.

In some embodiments, the aqueous base solution is an aqueous solution of sodium hydroxide, potassium hydroxide or lithium hydroxide. In other embodiments, the cosolvent is ethanol, methanol, isopropanol, THF, or dioxane.

In some embodiments, the methods further comprise preparing a compound of formula (IId)

<img file="00000059.jpg" he="33" wi="41" img-format="tif" img-content="undefined" />

methods include contacting a compound of formula (IIe)

<img file="00000060.jpg" he="33" wi="41" img-format="tif" img-content="undefined" />

with R¹NH₂ in an organic solvent in the presence of an organic base.

In one embodiment, the organic solvent is dioxane, THF, NMP, DMF, DMSO, ethanol, methanol or isopropanol. In other - the base is DIEA, TEA, N-methylmorpholine, 1,8-diazabicyclo [5.4.0] undec-7-ene, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium carbonate or potassium phosphate. In some embodiments, contacting is carried out at elevated temperature, e.g., about 80 ° C to about 100 ° C.

In some embodiments, the methods further comprise preparing a compound of formula (IIe)

<img file="00000061.jpg" he="35" wi="36" img-format="tif" img-content="undefined" />

methods include contacting a compound of formula (IIf)

<img file="00000062.jpg" he="28" wi="39" img-format="tif" img-content="undefined" />

с NaSR^x in an organic solvent in the presence of a catalyst.

In one embodiment, the solvent is THF, DCM or dioxane. In one embodiment the catalyst is trietilbenzilhlorid ammonium tetrabutilhlorid ammonium or tetrabutylammonium bromide. In some embodiments, contacting is carried out under cooling, for example at about -10 ° C.

In some embodiments, the methods further comprise preparing a compound of formula (IIb):

<img file="00000063.jpg" he="34" wi="34" img-format="tif" img-content="undefined" />

methods include contacting a compound of Formula (IIg)

<img file="00000064.jpg" he="30" wi="32" img-format="tif" img-content="undefined" />

with a peroxide in the presence of a base in a solvent.

In some embodiments, the solvent is DMSO, NMP, DMF, ethanol or methanol. In other - the base is sodium hydroxide or potassium hydroxide.

In some embodiments, the methods further comprise preparing a compound of formula (IIg)

<img file="00000065.jpg" he="33" wi="36" img-format="tif" img-content="undefined" />

methods include contacting a compound of formula (IIh)

<img file="00000066.jpg" he="29" wi="34" img-format="tif" img-content="undefined" />

and ditsianotsinkom with zinc in the presence of a catalyst in a solvent.

In some embodiments, the catalyst is a Pd (0). In some embodiments, the solvent is DMF, DMSO, NMP or DMA. In other - contacting is carried out at elevated temperature, e.g., at a temperature between about 80 ° C and about 100 ° C.

In some embodiments, the methods further comprise preparing a compound of formula (IIh)

<img file="00000067.jpg" he="28" wi="31" img-format="tif" img-content="undefined" />

methods include contacting a compound of formula (IIi)

<img file="00000068.jpg" he="28" wi="29" img-format="tif" img-content="undefined" />

with R¹NH₂In the presence of a base, in an organic solvent.

In some embodiments, the organic solvent is n-butanol, NMP, DMF, DMSO, dioxane or ethanol. In other - the base is DIEA, TEA, N-methylmorpholine, 1,8-diazabicyclo [5.4.0] undec-7-ene, potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate or potassium phosphate. In some embodiments, contacting is carried out at elevated temperature, e.g., at a temperature between about 80 ° C and about 100 ° C.

Also provided methods for preparing compounds of formula (I):

<img file="00000069.jpg" he="34" wi="39" img-format="tif" img-content="undefined" />

methods include contacting a compound of formula (IIIa)

<img file="00000070.jpg" he="34" wi="38" img-format="tif" img-content="undefined" />

с NH₄Cl, in the presence of a coupling agent and a base in a solvent, wherein:

R¹ represents substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted alkylcycloalkyl, or unsubstituted or substituted alkylheterocyclyl, provided that R¹ It is not 1-aminotsiklogeksilom; and

R² represents substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted saturated cycloalkyl, unsubstituted or substituted alkylcycloalkyl, unsubstituted or substituted non-aromatic heterocyclyl.

In one embodiment of the present invention, the compound of formula (I) is not 2- (2-aminoethylamino) -4- (methylamino) pyrimidine-5-carboxamide; 2- (2-aminopropylamino) -4- (cyclohexylamino) pyrimidine-5-carboxamide; 2- (2-amino-2-oxo-ethylamino) -4- (cyclohexylamino) pyrimidine-5-carboxamide; 2- (2-aminoethylamino) -4- (cyclohexylamino) pyrimidine-5-carboxamide; (S) -2- (2-aminopropylamino) -4- (cyclobutylamino) pyrimidine-5-carboxamide; (R) -2- (1-amino-3-methyl-1-oxobutan-2-ylamino) -4- (cyclobutylamino) pyrimidine-5-carboxamide; 4- (cyclopentylamino) -2- (methylamino) pyrimidine-5-carboxamide; or 2- (1-acetylpiperidin-4-ylamino) -4- (cyclopropylamino) pyrimidine-5-carboxamide.

In some embodiments, the solvent is NMP, DMF, DMSO, dioxane, THF, DCM or chloroform. In other - the binding agent is HATU, CDI, HBTU, EDC / HOBt or ethyl chloroformate, and the base is DIEA, TEA or potassium carbonate.

In some such embodiments, the methods further comprise preparing a compound of formula (IIIa):

<img file="00000071.jpg" he="34" wi="38" img-format="tif" img-content="undefined" />

methods include contacting a compound of formula (IIIb)

<img file="00000072.jpg" he="33" wi="41" img-format="tif" img-content="undefined" />

with an aqueous base solution in a cosolvent, where R^x It represents C_1-2 alkyl.

In some embodiments, the aqueous base solution is an aqueous solution of sodium hydroxide, potassium hydroxide or lithium hydroxide. In other embodiments, the cosolvent is ethanol, methanol, isopropanol, THF, or dioxane.

In some embodiments, the method further comprises preparing a compound of formula (IIIb):

<img file="00000073.jpg" he="33" wi="37" img-format="tif" img-content="undefined" />

the method comprising contacting a compound of formula (IIIc)

<img file="00000074.jpg" he="32" wi="38" img-format="tif" img-content="undefined" />

with R¹NH₂ in the presence of an organic base in an organic solvent.

In some embodiments, the organic solvent is THF, NMP, DMF, DMSO, dioxane, ethanol, methanol or isopropanol. In other - it is an organic base DIEA, TEA, 1,8-diazabicyclo [5.4.0] undec-7-ene, N-methylmorpholine, sodium carbonate, sodium bicarbonate, cesium carbonate or potassium phosphate. In some embodiments, contacting is carried out at elevated temperature, e.g., about 70 ° C.

In some embodiments, the methods further comprise preparing a compound of formula (IIIc)

<img file="00000075.jpg" he="34" wi="35" img-format="tif" img-content="undefined" />

methods include contacting a compound of formula (IIId)

<img file="00000076.jpg" he="28" wi="35" img-format="tif" img-content="undefined" />

with R²NH₂ in the presence of an organic base in a solvent.

In some embodiments, the solvent is ethyl ether, THF, DCM, toluene or methyl tert-butyl ether. In other - the base is DIEA, TEA, 1,8-diazabicyclo [5.4.0] undec-7-ene, N-methylmorpholine, sodium bicarbonate, cesium carbonate or potassium phosphate. In some embodiments, contacting is carried out at low temperature, e.g., about -70 ° C.

Also provided methods for preparing compounds of formula (I):

<img file="00000077.jpg" he="33" wi="37" img-format="tif" img-content="undefined" />

methods include contacting a compound of formula (IVa)

<img file="00000078.jpg" he="29" wi="46" img-format="tif" img-content="undefined" />

a peroxide catalyst, in the presence of an aqueous solution of a strong base, in a solvent, wherein:

R¹ represents substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted alkylcycloalkyl, or unsubstituted or substituted alkylheterocyclyl, provided that R¹ It is not 1-aminotsiklogeksilom; and

R² represents substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted saturated cycloalkyl, unsubstituted or substituted alkylcycloalkyl, unsubstituted or substituted non-aromatic heterocyclyl.

In one embodiment of the present invention, the compound of formula (I) does not represent a 2- (2-aminoethylamino) -4- (methylamino) pyrimidine-5-carboxamide; 2- (2-aminopropylamino) -4- (cyclohexylamino) pyrimidine-5-carboxamide; 2- (2-amino-2-oxo-ethylamino) -4- (cyclohexylamino) pyrimidine-5-carboxamide; 2- (2-aminoethylamino) -4- (cyclohexylamino) pyrimidine-5-carboxamide; (S) -2- (2-aminopropylamino) -4- (cyclobutylamino) pyrimidine-5-carboxamide, (R) -2- (1-amino-3-methyl-1-oxobutan-2-ylamino) -4- ( cyclobutylamino) pyrimidine-5-carboxamide; 4- (cyclopentylamino) -2- (methylamino) pyrimidine-5-carboxamide; or 2- (1-acetylpiperidin-4-ylamino) -4- (cyclopropylamino) pyrimidine-5-carboxamide.

In some embodiments, the solvent is DMSO, NMP, DMF, ethanol or methanol. In other - an aqueous solution of a strong base is such as sodium hydroxide or potassium hydroxide.

In some such embodiments, the methods further comprise preparing a compound of formula (IVa):

<img file="00000079.jpg" he="34" wi="41" img-format="tif" img-content="undefined" />

methods include contacting a compound of formula (IVb)

<img file="00000080.jpg" he="31" wi="36" img-format="tif" img-content="undefined" />

with R¹NH₂ in the presence of a base, in an organic solvent.

In some embodiments, the organic solvent is 1-butanol, THF, NMP, DMF, DMSO, dioxane, ethanol, methanol or isopropanol. In other - the base is cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate, 1,8-diazabicyclo [5.4.0] undec-7-ene, N-methylmorpholine, DIEA or TEA. In some embodiments, contacting is carried out at elevated temperature, e.g., about 120 ° C.

In some such embodiments, the methods further comprise preparing a compound of formula (IVb):

<img file="00000081.jpg" he="33" wi="36" img-format="tif" img-content="undefined" />

methods include contacting a compound of formula (IVc)

<img file="00000082.jpg" he="24" wi="31" img-format="tif" img-content="undefined" />

with R²NH₂ in the presence of a base, in an organic solvent.

In some embodiments, the organic solvent is ethanol, methanol, isopropanol or THF. In other - the base is DIEA, TEA, 1,8-diazabicyclo [5.4.0] undec-7-ene, N-methylmorpholine, sodium carbonate, sodium bicarbonate, cesium carbonate or potassium phosphate. In some embodiments, contacting is carried out at low temperature, e.g., about -60 ° C.

In some embodiments, the methods further comprise preparing a compound of formula (IVa):

<img file="00000083.jpg" he="32" wi="33" img-format="tif" img-content="undefined" />

methods include contacting a compound of formula (IVd)

<img file="00000084.jpg" he="31" wi="38" img-format="tif" img-content="undefined" />

with R²NH₂ in the presence of a base, in an organic solvent.

In some embodiments, the organic solvent is DCM, NMP, DMF or DMA. In other - the base is DIEA, TEA, 1,8-diazabicyclo [5.4.0] undec-7-ene or N-methylmorpholine. In some embodiments, contacting is carried out at a temperature between room temperature and about 130 ° C.

In some embodiments, the methods further comprise preparing a compound of formula (IVd):

<img file="00000085.jpg" he="32" wi="39" img-format="tif" img-content="undefined" />

oxidation methods include the compound of formula (IIg)

<img file="00000086.jpg" he="31" wi="35" img-format="tif" img-content="undefined" />

in a solvent by treatment with an oxidizing agent selected from mCPBA, Oxone, hydrogen peroxide or 3-phenyl-2- (phenylsulfonyl) -1,2-oxaziridine.

In one embodiment, the solvent is DCM, NMP, DMF or DMA. In some embodiments, oxidation is carried out at a temperature from about 0 ° C to about room temperature.

Also provided methods for preparing compounds of formula (IB)

<img file="00000087.jpg" he="30" wi="36" img-format="tif" img-content="undefined" />

methods include contacting a compound of formula (Va)

<img file="00000088.jpg" he="31" wi="34" img-format="tif" img-content="undefined" />

with R³NH₂ in the presence of a base, in an organic solvent, wherein

R³ represents substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted alkylcycloalkyl, or substituted or unsubstituted alkyl (non-aromatic heterocyclyl); and

R⁴ represents substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted non-aromatic heterocyclyl.

In one embodiment, the compound is not 4- (isopentylamino) -2- (3- (2-methylpiperidin-1-yl) propylamino) -pyrimidine-5-carbonitrile; (2S, 2'S) dimethyl 2,2 '- (5-cyanopyrimidin-2,4-diyl) bis (azanediil) bis (4-methylpentanoate); (2S, 2'S) diethyl 2,2 '- (5-cyanopyrimidin-2,4-diyl) bis (azanediil) bis (3-methylbutanoate); 4- (cycloheptylamino) -2- (3- (2-methylpiperidin-1-yl) propylamino) -pyrimidine-5-carbonitrile; 4- (4-methylcyclohexylamine) -2- (3- (2-methylpiperidin-1-yl) propylamino) -pyrimidine-5-carbonitrile; or 2- (3- (diethylamino) propylamino) -4- (4-methylcyclohexylamine) -pyrimidine-5-carbonitrile.

In some embodiments, the organic solvent is 1-butanol, THF, NMP, DMF, DMSO, dioxane, ethanol, methanol or isopropanol. In other - the base is cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate, 1,8-diazabicyclo [5.4.0] undec-7-ene, N-methylmorpholine, DIEA or TEA. In some embodiments, contacting is carried out at elevated temperature, e.g., about 50 ° C to about 90 ° C.

In some such embodiments, the methods further comprise preparing a compound of formula (Va):

<img file="00000089.jpg" he="32" wi="38" img-format="tif" img-content="undefined" />

methods include contacting a compound of formula (Vb)

<img file="00000090.jpg" he="26" wi="34" img-format="tif" img-content="undefined" />

with R⁴NH₂ in the presence of a base, in an organic solvent.

In some embodiments, the organic solvent is ethanol, methanol, isopropanol or THF. In other - the base is DIEA, TEA, 1,8-diazabicyclo [5.4.0] undec-7-ene, N-methylmorpholine, sodium carbonate, sodium bicarbonate, cesium carbonate or potassium phosphate. In some embodiments, contacting is carried out at low temperature, e.g., from about -70 ° C to about 20 ° C.

Also provided methods for preparing compounds of formula (IB)

<img file="00000091.jpg" he="31" wi="38" img-format="tif" img-content="undefined" />

methods include contacting a compound of formula (VIa)

<img file="00000092.jpg" he="31" wi="35" img-format="tif" img-content="undefined" />

with R⁴NH₂ in the presence of a base, in an organic solvent, wherein

R³ represents substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted alkylcycloalkyl, or substituted or unsubstituted alkyl (non-aromatic heterocyclyl); and

R⁴ represents substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted non-aromatic heterocyclyl.

In one embodiment, the compound is not 4- (isopentylamino) -2- (3- (2-methylpiperidin-1-yl) propylamino) -pyrimidine-5-carbonitrile; (2S, 2'S) dimethyl 2,2 '- (5-cyanopyrimidin-2,4-diyl) bis (azanediil) bis (4-methylpentanoate); (2S, 2'S) diethyl 2,2 '- (5-cyanopyrimidin-2,4-diyl) bis (azanediil) bis (3-methylbutanoate); 4- (cycloheptylamino) -2- (3- (2-methylpiperidin-1-yl) propylamino) -pyrimidine-5-carbonitrile; 4- (4-methylcyclohexylamine) -2- (3- (2-methylpiperidin-1-yl) propylamino) -pyrimidine-5-carbonitrile; or 2- (3- (diethylamino) propylamino) -4- (4-methylcyclohexylamine) -pyrimidine-5-carbonitrile.

In some embodiments, the organic solvent is 1-butanol, NMP, DMF, DMSO, or dioxane. In other - the base is cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate, 1,8-diazabicyclo [5.4.0] undec-7-ene, N-methylmorpholine, DIEA or TEA. In some embodiments, contacting is carried out at elevated temperature, e.g., about 25 ° C to about 110 ° C.

In some such embodiments, the methods further comprise preparing a compound of formula (VIa):

<img file="00000093.jpg" he="31" wi="31" img-format="tif" img-content="undefined" />

methods include contacting a compound of formula (Vb)

<img file="00000094.jpg" he="26" wi="30" img-format="tif" img-content="undefined" />

with R³NH₂ in the presence of a base, in an organic solvent.

In some such embodiments, the organic solvent is ethanol, methanol, isopropanol or THF. In other - the base is DIEA, TEA, 1,8-diazabicyclo [5.4.0] undec-7-ene, N-methylmorpholine, sodium carbonate, sodium bicarbonate, cesium carbonate or potassium phosphate. In some embodiments, contacting is carried out at low temperature, e.g., from about -70 ° C to about 20 ° C.

Methods are provided for preparing a compound of formula (IB)

<img file="00000095.jpg" he="29" wi="38" img-format="tif" img-content="undefined" />

methods include contacting a compound of formula (VIIa)

<img file="00000096.jpg" he="31" wi="39" img-format="tif" img-content="undefined" />

with R³NH₂ in the presence of a base, in an organic solvent, wherein

R³ represents substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted alkylcycloalkyl, or substituted or unsubstituted alkyl (non-aromatic heterocyclyl);

R⁴ represents substituted or unsubstituted C_1-8 alkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted non-aromatic heterocyclyl;

R^x It represents C_1-2 alkyl and

m is 1 or 2.

In one embodiment, the compound is not 4- (isopentylamino) -2- (3- (2-methylpiperidin-1-yl) propylamino) -pyrimidine-5-carbonitrile; (2S, 2'S) dimethyl 2,2 '- (5-cyanopyrimidin-2,4-diyl) bis (azanediil) bis (4-methylpentanoate); (2S, 2'S) diethyl 2,2 '- (5-cyanopyrimidin-2,4-diyl) bis (azanediil) bis (3-methylbutanoate); 4- (cycloheptylamino) -2- (3- (2-methylpiperidin-1-yl) propylamino) -pyrimidine-5-carbonitrile; 4- (4-methylcyclohexylamine) -2- (3- (2-methylpiperidin-1-yl) propylamino) -pyrimidine-5-carbonitrile; or 2- (3- (diethylamino) propylamino) -4- (4-methylcyclohexylamine) -pyrimidine-5-carbonitrile.

In one embodiment the solvent is dioxane, DMSO, NMP, DMF, THF or n-butanol. In another - the base is DIEA, TEA, 1,8-diazabicyclo [5.4.0] undec-7-ene, N-methylmorpholine. In some embodiments, contacting is carried out at elevated temperature, e.g., about 25 ° C to about 110 ° C.

In some embodiments, the methods further comprise preparing a compound of formula (VIIa):

<img file="00000097.jpg" he="33" wi="36" img-format="tif" img-content="undefined" />

oxidation methods include the compound of formula (VIIb)

<img file="00000098.jpg" he="30" wi="36" img-format="tif" img-content="undefined" />

in a solvent by treatment with an oxidizing agent selected from mCPBA, Oxone, hydrogen peroxide or 3-phenyl-2- (phenylsulfonyl) -1,2-oxaziridine.

In one embodiment, the solvent is DCM, NMP, DMF or DMA. In some embodiments, oxidation is carried out at a low temperature, for example at about 0 ° C.

In some embodiments, the methods further comprise preparing a compound of formula (VIIb)

<img file="00000099.jpg" he="33" wi="39" img-format="tif" img-content="undefined" />

methods include contacting a compound of formula (VIIc)

<img file="00000100.jpg" he="26" wi="37" img-format="tif" img-content="undefined" />

with R⁴NH₂ in an organic solvent in the presence of a base.

In one embodiment of the present invention, the organic solvent is n-butanol, NMP, DMF, DMSO, or dioxane. In another, the base is DIEA, TEA, N-methylmorpholine, 1,8-diazabicyclo [5.4.0] undec-7-ene, potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate or potassium phosphate. In some embodiments, contacting is carried out at elevated temperature, e.g., about 50 ° C to about 90 ° C.

Methods of Use

Diaminopirimidinovye compounds can be used as pharmaceuticals for treatment, prevention or amelioration of states in animals and humans. Furthermore, diaminopirimidinovye compounds are active against protein kinases, in particular, JNK1 and / or JNK2. Thus, in the present specification shows a large number of options to apply diaminopirimidinovyh compounds, including the treatment or prevention of diseases mentioned below. The methods of the present disclosure include administration of an effective amount of one or more compounds diaminopyrimidine (s) to the individual in need thereof.

In one aspect, methods of inhibiting kinases listed in a cell expressing said kinase, comprising contacting said cell with an effective amount diaminopirimidinovogo compound. In one embodiment of the present invention is a kinase JNK1, JNK2, or their mutants or isoforms or a combination thereof. For example, a diaminopyrimidine compound is a compound of Table 1, 2 or 3.

In another aspect, methods are provided for treating or preventing liver fibrotic diseases such as NASH, steatosis (i.e., fatty liver), cirrhosis, primary sclerosing cholangitis, primary biliary cirrhosis, hepatitis, hepatocellular carcinoma or liver fibrosis associated with chronic or repeated use alcohol (alcoholic hepatitis), infection (e.g., viral infection, such as HCV), liver transplant or a liver disease caused by the intake of drugs (e.g. tsetaminofenovaya toxicity), comprising administering to the individual in need thereof an effective amount of a compound diaminopirimidinovogo. In some such aspects, the present description provides methods of treating or preventing diabetes or metabolic syndrome,

In another aspect, the description provides methods of treating or preventing one or more diseases selected from interstitial lung fibrosis, systemic sclerosis, scleroderma, chronic allograft nephropathy, antibody mediated rejection or lupus, comprising administering to the individual in need thereof an effective amount of a compound diaminopirimidinovogo. In some such embodiments, the lupus is lupus (discoid shape such as lupus erythematosus or cutaneous lupus erythematosus) or systemic lupus.

In another aspect, the description provides methods for the treatment or prophylaxis of conditions, the treatment or prevention of which is possible by the inhibition of JNK1 and / or JNK2, the method comprises administering to the individual in need thereof an effective amount of a compound diaminopirimidinovogo. Examples of such conditions include rheumatoid arthritis; rheumatoid spondylitis; osteoarthritis; asthma, bronchitis; allergic rhinitis; chronic obstructive pulmonary disease; cystic fibrosis; inflammatory bowel disease; irritable bowel syndrome; irritable bowel syndrome; ulcerative colitis; Crohn's disease; Huntington's disease; hepatitis; pancreatitis; nephritis; multiple sclerosis; lupus erythematosus, diabetes type II; obesity; atherosclerosis; restenosis after angioplasty; left ventricular hypertrophy; myocardial infarction; stroke; ischemic damage to the heart, lungs, intestines, kidney, liver, pancreas, spleen and brain; acute or chronic organ transplant rejection; organ preservation for transplantation; organ failure or loss of limb (for example, but not limited to, due to ischemic reperfusion, a serious injury of the body, a car accident, crush syndrome or transplant failure); reaction "transplant versus host"; endotoxin shock; multiple organ failure; psoriasis; burn when exposed to fire, chemicals or radiation; eczema; dermatitis; Skin transplant; ischemia; ischemic conditions associated with surgery or traumatic injury (e.g., traffic accidents, gunshot wound or limb damage); epilepsy; Alzheimer's disease; Parkinson's disease; immunological response to bacterial or viral infection; cachexia; angiogenic and proliferative diseases; solid tumor; and zlokachstvennye tumors of various tissues such as the colon, rectum, prostate, liver, lung, bronchus, pancreas, brain, head, neck, stomach, skin, kidney, cervix, blood, larynx, esophagus, oral cavity , pharynx, urinary bladder, ovary or uterus.

Pharmaceutical compositions and routes of administration

Diaminopirimidinovye compounds can be administered to a subject orally, topically or parenterally in a convenient form preparations, such as capsules, microcapsules, tablets, granules, powder, Trochu pillyuli, suppositories, injections, suspensions, syrups, plasters, creams, lotions, ointments, gels, sprays, solutions and emulsions. Suitable formulations may be prepared by widely used methods using organic or inorganic additives, such as excipient (e.g. sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate), binding agent (e.g. cellulose , methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethyleneglycol, sucrose or starch), a disintegrant (e.g., starch, carboxymethylcellulose, hydroxypropyl starch, low-substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate or calcium citrate), a lubricant (e.g., magnesium stearate, light anhydrous silicic acid, talc or sodium lauryl sulfate), a flavoring agent (e.g. citric acid, methanol, glycine or orange-powder ), a preservative (e.g., sodium benzoate, sodium bisulfite, methylparaben or propylparaben), a stabilizer (e.g., citric acid, sodium citrate or acetic acid), suspending agent (e.g., methylcellulose, polyvinylpyrrolidone or aluminum minutes stearate), a dispersing agent (e.g., hydroxypropylmethylcellulose), a diluent (e.g., water), and base wax (e.g., cocoa butter, white petrolatum or polyethylene glycol). Diiaminopirimidinovyh effective amount of the compounds in the pharmaceutical composition may be at a level which will give the desired effect; e.g., from about 0.005 mg / kg of the individual's body weight to about 10 mg / kg body weight of the individual in a dosage form for oral and parenteral administration.

The dose administered to the individual diaminopirimidinovogo compound is in a sufficiently wide range and may be left to the discretion of a medical professional. Mainly diaminopirimidinovye compounds can be administered to the individual from one to four times a day in a dose of from about 0.005 mg / kg of the individual's body weight to about 10 mg / kg body weight of the individual body, but higher doses may accurately vary depending on the age, body weight and the individual's disease, and type of administration. In one embodiment the dose is from about 0.01 mg / kg body weight of the individual to about 5 mg / kg body weight of the individual, about 0.05 mg / kg of the individual's body weight to about 1 mg / kg body weight of the individual, about 0.1 mg / kg body weight of the individual to about 0.75 mg / kg body weight of the individual, or about 0.25 mg / kg of the individual's body weight to about 0.5 mg / kg body weight of the individual. In one embodiment of the present invention, one dose per day is calculated. In each case the amount diaminopyrimidine compound administered will depend on such factors as the solubility of the active substance composition and route of administration. In one embodiment, the present invention provides the topical application of impact or intracellular concentration of about 0.01-10 uM.

In yet another embodiment, the specification provides methods of treating or preventing a disease or disorder, comprising administering from about 0.375 mg / day to about 750 mg / day, about 0.75 mg / day to about 375 mg / day, about 3.75 mg / day to about 75 mg / day, about 7.5 mg / day to about 55 mg / day or about 18 mg / day to about 37 mg / day of compound diaminopirimidinovogo individual in need thereof.

In yet another embodiment, the description provides methods for treating or preventing a disease or disorder comprising administering from about 1 mg / day to about 1200 mg / day, about 10 mg / day to about 1200 mg / day, about 100 mg / day to about 1200 mg / day, about 400 mg / day to about 1200 mg / day, about 600 mg / day to about 1200 mg / day, about 400 mg / day to about 800 mg / day, or about 600 mg / day to about 800 mg / day diaminopirimidinovogo link requires that individual. In specific embodiments, the methods described herein comprise administering 400 mg / day, 600 mg / day or 800 mg / day of compound diaminopirimidinovogo individual in need thereof.

In yet another embodiment herein presented dosage forms that contain from about 1 mg to about 200 mg, from about 35 mg to about 1400 mg, from about 125 mg to about 1000 mg, from about 250 mg to about 1000 mg or from about 500 mg to about 1000 mg diaminopirimidinovogo compound.

In a specific embodiment herein presented dosage forms containing from about 100 mg or 400 mg diaminopirimidinovogo compound.

In yet another embodiment herein presented dosage forms that comprise 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 50 mg, 70 mg, 100 mg, 125 mg, 140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350 mg, 500 mg, 560 mg, 700 mg, 750 mg, 1000 mg or 1400 mg diaminopirimidinovogo compound.

Diaminopirimidinovoe compound may be administered one, two, three, four or more times per day. In a particular embodiment, doses of 600 mg or less are administered in a single dose once a day, and a dose of 600 mg administered twice a day in an amount equivalent to half of the total daily dose.

Diaminopirimidinovoe compound may be administered orally, given the convenience of application. In one embodiment of the present invention in oral administration diaminopirimidinovoe compound is administered with food or water. In yet another embodiment diaminopyrimidine compound is dispersed in water or juice (e.g., apple juice or orange juice) and administered orally as a suspension.

Compound diaminopyrimidine can also be administered intradermally, intramuscularly, intraperitoneally, subcutaneously, intravenously, intradermally, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, mucosally, by inhalation, or applied topically to the ears, nose, eyes, or skin. The choice of route of administration is left for a medical professional, and it may partly depend on the affected area.

In one embodiment, presented herein capsules containing diaminopirimidinovoe Compound without an additional carrier, excipient or filler.

In yet another embodiment, the specification provides compositions comprising an effective amount diaminopirimidinovogo compound and a pharmaceutically acceptable carrier or excipient, wherein the pharmaceutically acceptable carrier or vehicle can comprise an excipient, diluent or mixture thereof. In one embodiment the composition is a pharmaceutical composition.

The composition may be in the form of tablets, chewing tablets, capsules, solutions, parenteral solutions, Trochu, suppositories and suspensions, and the like. The composition may be formulated to contain a daily dose or an appropriate part of the daily dose, in a dosage form which may be a single tablet or capsule or a liquid in a suitable volume. In one embodiment, solutions are prepared from water-soluble salts such as the hydrochloride. In general, all compositions prepared in accordance with known techniques of pharmaceutical chemistry. Capsules can be prepared by mixing diaminopirimidinovogo compound with a suitable carrier or diluent and filler in an appropriate amount of the mixture in capsules. Conventional carriers and diluents include, but are not limited to,

Tablets may be prepared by direct compression, by wet granulation, or by dry granulation. Their formulations addition compounds generally include diluents, binders, lubricants and disintegrating agents. Common diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or calcium sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives may also be used. Conventional binders for tablets are substances such as starch, gelatin and sugars such as lactose, fructose, glucose and the like. Natural and synthetic waxes are also useful, including acacia, alginates, methylcellulose, polyvinylpyrrolidine and the like. polyethylene glycol, ethylcellulose and waxes can also serve as binders. Polyethylene glycol, ethylcellulose and waxes can also serve as binding agents.

In the tablet lubricant may be necessary to protect the tablets from sticking and punching in the dye. The lubricant can be chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and the anhydrous vegetable oil. Tablet disintegrators are substances which swell when wetted to break up the tablet and release the compound. They include starches, clays, celluloses, algins and wax. In particular, corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp and carboxymethylcellulose, for example, can also be employed with sodium lauryl sulphate. The tablets may be coated with sugar as a sweetener and sealant, or with filmforming protecting agent to modify the dissolution properties of the tablet. The compositions may also be formulated as chewable tablets, for example, using a composition of matter, such as mannitol.

If desired diaminopirimidinovoe compound administered as a suppository, the usual bases may be used. Cocoa butter is a traditional suppository base, which may be modified by addition of waxes to slightly increase the melting point. Widely used in a water-miscible suppository bases comprising, particularly, polyethylene glycols of various molecular weights.

Due to the effect of a suitable composition diaminopirimidinovogo compounds may be delayed or prolonged. For example, they can be prepared and formulated into tablets or capsules slowly soluble pellet-diaminopyrimidine compound, or as a slow-releasing implantable means. The technique also involves the preparation of pellets of several different levels of soluble and filling capsules with a mixture of pellets. Tablets or capsules may be coated with a film which prevents dissolution for a predetermined period of time predicted. Even the parenteral preparations may be long-acting by dissolving or suspending the compound in oily or diaminopyrimidine emulsified media that oblespechivayut slow dissolution in serum.

EXAMPLES

The following examples are given as illustration and not limitation. The compounds identified with the name of the program from the automatic Chemdraw Ultra 9,0 (CambridgeSoft), which generates the systematic names for chemical structures with support for rules Cahn-Ingold-Prelog rules for stereochemistry. One skilled in the art can modify the procedures set forth in the illustrative examples to obtain the desired products.

The following abbreviations:

<tables num="1"><table frame="none"><tgroup rowsep="0" colsep="0" cols="2"><colspec colname="c1" colwidth="70mm" /><colspec colname="c2" colwidth="70mm" /><tbody><row><entry align="left" rowsep="0" colsep="0">DCM</entry><entry align="right" rowsep="0" colsep="0">dichloromethane</entry></row><row><entry align="left" rowsep="0" colsep="0">DEA</entry><entry align="right" rowsep="0" colsep="0">diethylamine</entry></row><row><entry align="left" rowsep="0" colsep="0">DIEA</entry><entry align="right" rowsep="0" colsep="0">N, N-diizopropilэtilamin</entry></row><row><entry align="left" rowsep="0" colsep="0">DMA</entry><entry align="right" rowsep="0" colsep="0">N, N-dimethylacetamide</entry></row><row><entry align="left" rowsep="0" colsep="0">KAP</entry><entry align="right" rowsep="0" colsep="0">N, N-dimethylformamide</entry></row><row><entry align="left" rowsep="0" colsep="0">DMSO</entry><entry align="right" rowsep="0" colsep="0">dimetilsulyfoksid</entry></row><row><entry align="left" rowsep="0" colsep="0">EDC</entry><entry align="right" rowsep="0" colsep="0">hydrochloride, ethyl- (N ', N'-dimethylamino) propyl carbodiimide</entry></row><row><entry align="left" rowsep="0" colsep="0">ESI</entry><entry align="right" rowsep="0" colsep="0">electrospray ionization</entry></row><row><entry align="left" rowsep="0" colsep="0">HATU</entry><entry align="right" rowsep="0" colsep="0">гексафторфосфат O- (7-азабензотриазол-1-ил) -N, N, N ', N'-тетраметилурония </entry></row><row><entry align="left" rowsep="0" colsep="0">HOBt</entry><entry align="right" rowsep="0" colsep="0">1-hydroxybenzotriazole</entry></row><row><entry align="left" rowsep="0" colsep="0">VEJKh</entry><entry align="right" rowsep="0" colsep="0">High performance liquid chromatography</entry></row><row><entry align="left" rowsep="0" colsep="0">Htrf</entry><entry align="right" rowsep="0" colsep="0">homogeneous time-resolved fluorescence</entry></row><row><entry align="left" rowsep="0" colsep="0">ЖХ-MS</entry><entry align="right" rowsep="0" colsep="0">Liquid chromatography with mass spectrometry</entry></row><row><entry align="left" rowsep="0" colsep="0">mCPBA</entry><entry align="right" rowsep="0" colsep="0">meta hlorperoksybenzoynaya acid</entry></row><row><entry align="left" rowsep="0" colsep="0">MC</entry><entry align="right" rowsep="0" colsep="0">Mass spectrometry</entry></row><row><entry align="left" rowsep="0" colsep="0">NMP</entry><entry align="right" rowsep="0" colsep="0">N-метилпирролидон</entry></row><row><entry align="left" rowsep="0" colsep="0">YaMR</entry><entry align="right" rowsep="0" colsep="0">nuclear magnetic resonance</entry></row><row><entry align="left" rowsep="0" colsep="0">SFC</entry><entry align="right" rowsep="0" colsep="0">chromatography with supercritical mobile phase</entry></row><row><entry align="left" rowsep="0" colsep="0">TBTU</entry><entry align="right" rowsep="0" colsep="0">O-бензотриазол-1-ил-N, N, N ', N'-тетра-метилуроний тетрафторборат</entry></row><row><entry align="left" rowsep="0" colsep="0">Feasibility Study</entry><entry align="right" rowsep="0" colsep="0">triethylamine</entry></row><row><entry align="left" rowsep="0" colsep="0">TFU</entry><entry align="right" rowsep="0" colsep="0">trifluoroacetic acid</entry></row><row><entry align="left" rowsep="0" colsep="0">TGF</entry><entry align="right" rowsep="0" colsep="0">tetrahydrofuran</entry></row><row><entry align="left" rowsep="0" colsep="0">TLC</entry><entry align="right" rowsep="0" colsep="0">TLC</entry></row></tbody></tgroup></table></tables>

synthesis of compounds

Example 1: 4 - ((1R, 3R) -3-gidroksiciklogeksilamino) -2 - ((1R, 4R) -4-metoksiciklogeksilamino) pyrimidine-5-carboxamide

<img file="00000101.jpg" he="32" wi="51" img-format="tif" img-content="undefined" />

4-Chloro-2 - ((1R, 4R) -4-metoksitsiklogeksilamino) -pyrimidine-5-carbonitrile. 2,4-Dichloropyrimidin-5-carbonitrile (1.2 g, 6.93 mmol) in anhydrous ethanol (10 mL) and (1R, 4R) -4-metoksitsiklogeksanamin (893 mg, 6.93 mmol) in anhydrous ethanol ( 10 ml) was stirred at -60 ° C, followed by dropwise addition of DIEA (1.34 g, 10.4 mmol). The mixture was stirred at -60 ° C for 1.5 hours then at room temperature overnight. Volatile fractions were removed and the residue was purified on silica gel (eluting with 9.1% -25% ethyl acetate in petroleum ether, and 3.2% -4.7% methanol in DCM) to give 2 isomers (identified as described below), namely 4-chloro-2 - ((1R, 4R) -4-metoksitsiklogeksilamino) -pyrimidine-5-carbonitrile (560 mg, 2.10 mmol, yield 30%) as a white solid and 2-chloro-4 - ((1R , 4R) -4-metoksitsiklogeksilamino) -pyrimidine-5-carbonitrile (227 mg, 0.85 mmol, yield 12%) as a white solid. MC (ESI): m / z 266,9 [M + 1]⁺.

Identification of the two isomers was performed by characteristics dehalogenated intermediate. Dehalogenation of the two fractions was conducted as follows. 4-Chloro-2 - ((1R, 4R) -4-metoksitsiklogeksilamino) -pyrimidine-5-carbonitrile (50 mg, 0.18 mmol) and Raney nickel in THF co-solvent (10 ml) and aqueous ammonia solution (1 ml) was stirred at room temperature under hydrogen balloon overnight. The mixture was filtered and the filtrate was concentrated and purified by preparative reverse phase HPLC (10% -40% Acetonitrile + 0.005% ammonium solution) to give 5- (aminomethyl) -N - ((1R, 4R) -4-methoxycyclohexyl) pyrimidine -2-amine (25 mg, 0.10 mmol, yield 58%).¹H-ЯМР (CDCl₃ 300 MHz):. Δ h / million 8.23 ​​(s, 2H), 4.96 (d, J = 10,0 Hz, 1H), 3,85-3,73 (m, 1H), 3.69 (s, 2H), 3.34 (s, 3H), 3,22-3,11 (m, 1H), 2,15-2,04 (m, 4H), 1,44-1,34 (m , 4H); MC (ESI): m / z 236,9 [M + 1]⁺.

Similarly, 2-chloro-4 - ((1R, 4R) -4-metoksitsiklogeksilamino) -pyrimidine-5-carbonitrile (50 mg, 0.18 mmol) and Raney nickel in THF co-solvent (10 ml) and aqueous ammonia solution (1 ml ) was stirred at room temperature under hydrogen balloon overnight. The mixture was filtered and the filtrate was concentrated and purified by preparative reverse phase HPLC (10% -40% Acetonitrile + 0.005% ammonium solution) to give 5- (aminomethyl) -N - ((1R, 4R) -4-methoxycyclohexyl) pyrimidine -4-amine (30 mg, 0.12 mmol, yield 66%).¹Н-ЯМР (CDCl₃ 300 MHz):. Δ h / million 8.46 (s, 1H), 7.84 (s, 1H), 7.25 (s, 1H), 4,00-3,93 (m, 1H), 3 79 (s, 2H), 3.34 (s, 3H), 3,23-3,14 (m, 1H), 2.14-2.02 (m, 4H), 1,48-1,22 (m, 4H); MC (ESI): m / z 236,9 [M + 1]⁺.

B. 4 - ((1R, 3R) -3-hydroxycyclohexylamino) -2 - ((1R, 4R) -4-metoksitsiklogeksilamino) -pyrimidine-5-carbonitrile. A mixture of 4-chloro-2 - ((1R, 4R) -4-metoksitsiklogeksilamino) -pyrimidine-5-carbonitrile (236 mg, 0.88 mmol), (1R, 3R) -3-aminocyclohexanol (151 mg, 1.32 mmol ; prepared as described in Tetrahedron: Asymmetry 15: 2051-2056 (2004)) and cesium carbonate (573 mg, 1.76 mmol) in anhydrous n-butanol (20 ml) was stirred at 120 ° C under a nitrogen atmosphere for 3 h . The mixture was partitioned between water and DCM. The organic layers were combined, concentrated and purified on silica gel (eluting with 16% -50% ethyl acetate in petroleum ether, and 3.2% -4.7% methanol in DCM) to give 4 - ((1R, 3R) -3-hydroxycyclohexylamino) - 2 - ((1R, 4R) -4-metoksitsiklogeksilamino) -pyrimidine-5-carbonitrile (140 mg, 0.40 mmol, yield 46%) as a white solid. MC (ESI): m / z 346,0 [M + 1]⁺.

C. 4 - ((1R, 3R) -3-Gidroksiciklogeksilamino) -2 - ((1R, 4R) -4-metoksiciklogeksilamino) pyrimidine-5-carboxamide. 4 - ((1R, 3R) -3-Gidroksiciklogeksilamino) -2 - ((1R, 4R) -4-metoksiciklogeksilamino) pyrimidine-5-carbonitrile (140 mg, 0.40 mmol) rastvorâli in DMSO (10 ml) and dobavlâli in komnatnoj temperature ten drops of the solution to water eventful gidroksida Sodium and ten drops of solution to water perekisi hydrogen (30%). Reakcionnuû peremešivali mix at 50 ° C for 6 h. Reakcionnuû blend worked between DCM and water-isopropanol (5: 1). Organic layers obʺedinâli, koncentrirovali and Cleansing on silica gel (élûiruâ 50% -75% ethyl acetate in Broadcasted petroleumsulfonates and 4.76% -9.1% methanol in DCM) with receipt of 4 - ((1R, 3R) -3-gidroksiciklogeksilamino) - 2 - ((1R, 4R) -4-metoksiciklogeksilamino) pyrimidine-5-carboxamide (103 mg, 0.28 mmol, 70% output) in the form of a rigid white substances.¹Н-ЯМР (ie ДМСО₆ 400 MHz): δ h / million 9.00 (d, J = 5,2 Hz, 1H), 8.33 (s, 1H), 7.54 (br s, 1H), 7.00 (s.. , 1H), 6.81 (s, 1H), 4.47 (s, 1H), 4.28 (s, 1H), 3.81 (s, 1H), 3.63 (s, 1H), 3 22 (s, 3H), 3.08 (s, 1H), 1,98-1,54 (m, 8H), 1,41-1,14 (m, 7H); MC (ESI): m / z 363,9 [M + 1]⁺.

Example 2: 4 - ((1S, 3S) -3-Gidroksiciklogeksilamino) -2 - ((1R, 4S) -4-metoksiciklogeksilamino) pyrimidine-5-carboxamide

<img file="00000102.jpg" he="31" wi="50" img-format="tif" img-content="undefined" />

A. 4 - ((1S, 3S) -3-hydroxycyclohexylamino) -2 - ((1R, 4S) -4-metoksitsiklogeksilamino) -pyrimidine-5-carbonitrile. A mixture of 4-chloro-2 - ((1R, 4R) -4-metoksitsiklogeksilamino) -pyrimidine-5-carbonitrile (236 mg, 0.88 mmol, synthesis described herein), (1S, 3S) -3-aminocyclohexanol (209 mg, 1.33 mmol; prepared as described in Tetrahedron: Asymmetry 15: 2051-2056 (2004)) and cesium carbonate (573 mg, 1.76 mmol) in anhydrous n-butanol (20 ml) was stirred at 120 ° C under a nitrogen atmosphere for 3 hours. The mixture was partitioned between water and DCM. The organic layers were combined, concentrated and purified on silica gel (eluting with 16% -50% ethyl acetate in petroleum ether, and 3.2% -4.7% methanol in DCM) to give 4 - ((1S, 3S) -3-hydroxycyclohexylamino) - 2 - ((1R, 4S) -4-metoksitsiklogeksilamino) -pyrimidine-5-carbonitrile (140 mg, 0.40 mmol, yield 46%) as a white solid. MC (ESI):⁺.

B. 4 - ((1S, 3S) -3-hydroxycyclohexylamino) -2 - ((1R, 4S) -4-metoksitsiklogeksilamino) pyrimidine-5-carboxamide. 4 - ((1S, 3S) -3-hydroxycyclohexylamino) -2 - ((1R, 4S) -4-metoksitsiklogeksilamino) -pyrimidine-5-carbonitrile (140 mg, 0.40 mmol) was dissolved in DMSO (10 mL) and at room temperature, ten drops of a saturated aqueous solution of sodium hydroxide and ten aqueous solution of hydrogen peroxide drops (30%). The reaction mixture was stirred at 50 ° C for 6 hours, the reaction mixture was partitioned between water and DCM-isopropanol (5: 1).. The organic layers were combined, concentrated and purified on silica gel (zlyuiruya 50% -75% ethyl acetate in petroleum ether, and 4.76% -9.1% methanol in DCM) to give 4 - ((1S, 3S) -3-hydroxycyclohexylamino) - 2 - ((1R, 4S) -4-metoksitsiklogeksilamino) pyrimidine-5-carboxamide (102 mg, 0.28 mmol, 70% yield) as a white solid.¹Н-ЯМР (ie ДМСО₆ 400 MHz): δ h / million 9.01 (d, J = 6,0 Hz, 1H), 8.34 (s, 1H), 7.56 (br s, 1H), 7.02 (d.. , J = 4,8 Hz, 1H), 6.82 (s, 1H), 4.48 (s, 1H), 4.29 (s, 1H), 3.81 (s, 1H), 3.64 (s, 1H), 3.23 (s, 3H), 3.08 (s, 1H), 2,01-1,55 (m, 8H), 1,41-1,15 (m, 7H); MC (ESI): m / z 363,9 [M + 1]⁺.

Example 3: 2 - ((1R, 4S) -4-Etoksitsiklogeksilamino) -4 - ((1S, 2S) -2-gidroksitsiklopentilamino) pyrimidine-5-carboxamide

<img file="00000103.jpg" he="29" wi="52" img-format="tif" img-content="undefined" />

A. tert-Butyl (1R, 4R) -4-gidroksitsiklogeksilkarbamat. To a suspension of (1R, 4R) -4-aminocyclohexanol (25 g, 217 mmol) in dioxane (200 ml) was added a solution of sodium hydroxide (8.7 g, 217 mmol) in water (150 ml) at room temperature and then was added di-tert-butyl dicarbonate (47 g, 270 mmol). The resulting mixture was stirred at room temperature for 15 hours. After starting material was consumed, the volatiles were removed and the residue diluted with water. The solid was collected by filtration and dried to obtain tert-butyl- (1R, 4R) -4-gidroksitsiklogeksilkarbamata as a white solid (33 g, 0.15 mol, 92% yield).¹Н-ЯМР (ie ДМСО₆, 300 MHz): δ h / million 6.65 (d, J = 7,5 Hz, 1H), 4.48 (d, J = 3,0 Hz, 1H), 3.14 (s, 1H). , 1.77 (m, 4H), 1,37 (s, 9H), 1.14 (m, 4H).

B. Tert-butyl (1R, 4R) -4-etoksitsiklogeksilkarbamat. The solution of tert-butyl (1R, 4R) -4-gidroksitsiklogeksilkarbamata (20 g, 93 mmol) in anhydrous THF (100 ml) was added portionwise sodium hydride (4 g, 100 mmol, 60% in mineral oil) under nitrogen at 0 ° C. The mixture was warmed to room temperature and stirred for 30 min. The mixture was added dropwise iodoethane solution (16 g, 102 mmol) in anhydrous THF (50 mL) at 0 ° C, and the resulting mixture was heated at 60 ° C for 15 hours. The mixture was cooled to room temperature and poured into water ice (100 mL). The aqueous admixture was extracted with ethyl acetate (100 ml × 3), and the organic phase was washed with saturated brine, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo.¹H-ЯМР (ДМСО-d₆, 400 MHz):. Δ h / million 6.70 (d, J = 7,6 Hz, 1H), 3.42 (q, J = 7,2 Hz, 2H), 3.11-3.17 ( m, 2H), 1.92 (m, 2H), 1.74 (m, 2H), 1.37 (s, 9H), 1.21 (m, 4H), 1.07 (t, J = 7 , 2 Hz, 3H).

C. The hydrochloride of (1R, 4R) -4-etoksitsiklogeksanamina. A solution of tert-butyl (1R, 4R) -4-etoksitsiklogeksilkarbamata (3.7 g, 15 mmol) in methanolic hydrogen chloride (2 M, 20 mL) was stirred at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure to give the hydrochloride (1R, 4R) -4-etoksitsiklogeksanamina (2.7 g, yield 100%).

D. hydrochloride (1S, 2S) -2-aminocyclopentanol. To a solution of (1S, 2S) -2- (benzyloxy) tsiklopentanamina (4.5 g, 22 mmol) and hydrochloric acid (0.5 ml) in methanol (100 ml) was added 10 wt. % Palladium on charcoal (500 mg). The mixture was stirred at room temperature under a hydrogen atmosphere (40 psi. Inch) for 24 hr. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to obtain (1S, 2S) -2-aminocyclopentanol as a white solid (2 14 g, 15 mmol, 93% yield).

E. Ethyl 4 - ((1S, 2S) -2-gidroksitsiklopentilamino) -2- (methylthio) pyrimidine-5-carboxylate. A mixture of ethyl 4-chloro-2- (methylthio) pyrimidine-5-carboxylate (1.4 g, 6.0 mmol), (1S, 2S) -2-aminocyclopentanol (0.7g, 6.9 mmol) and DIEA (1.0 g) in ethanol (20 ml) was heated at 60 ° C for 15 hours. After cooling at room temperature, the reaction solution was concentrated, and the residue was purified on a silica gel column (eluting with 0 ~ 10% ethyl acetate in petroleum ether ) to afford ethyl 4 - ((1S, 2S) -2-gidroksitsiklopentilamino) -2- (methylthio) pyrimidine-5-carboxylate (1.3 g, 4.37 mmol, yield 73%) as a white solid. MS (ESI): m / z 298,5 [M + 1]⁺.

F. 4 - ((1S, 2S) -2-Gidroksitsiklopentilamino) -2- (methylthio) pyrimidine-5-carboxylic acid. The solution of ethyl 4 - ((1S, 2S) -2-gidroksitsiklopentilamino) -2- (methylthio) pyrimidine-5-carboxylate (1.3 g, 4.37 mmol) in ethanol (15 mL) was added aqueous sodium hydroxide (15 ml, 2N) and the mixture was stirred for 1 hour at room temperature. After the starting material was consumed, the reaction mixture was neutralized with a saturated aqueous solution of citric acid. The solids were collected by filtration and dried to give 4 - ((1S, 2S) -2-gidroksitsiklopentilamino) -2- (methylthio) pyrimidine-5-carboxylic acid (1.0 g, 3.7 mmol, yield 85%) as a white solid. MS (ESI): m / z 270,6 [M + 1]⁺.

G. 4 - ((1S, 2S) -2-Gidroksiciklopentilamino) -2- (methylthio) pyrimidine-5-carboxamide. A mixture of 4 - ((1S, 2S) -2-gidroksiciklopentilamino) -2- (methylthio) pyrimidine-5-karbonovoj acids (1.0 g, 3.7 mmol), ammonium chloride (0.989 g, 18.5 mmol), HATU (2.25 g, 5.92 mmol), DIEA (2.39 g, 18.5 mmol) and 1-HOBt (0.80 g, 5.92 mmol) in DMF (10 ml) at peremešivali temperature komnatnoj in week 2 h. Reakcionnuû blend razbavlâli water (15 ml), and aquatic blend ékstragirovali ethyl acetate (20 ml × 3). Émirats organic layers promyvali nasyŝennym solevym solution, dried over sodium sulphate and filʹtrovali. The filtrate paired in a vacuum. Cleansing tire on the column with silica gel (30-50% ethyl acetate élûiruâ in petroleumsulfonates eter) with receipt of 4 - ((1S, 2S) -2-gidroksiciklopentilamino) -2- (methylthio) pyrimidine-5-carboxamide (800 mg, 2.98 mmol, yield: 81%) as a white solid. MS (ESI): m / z 269,4 [M + 1]⁺.

N. 4 - ((1S, 2S) -2-Gidroksiciklopentilamino) -2- (methylsulfonyl) pyrimidine-5-carboxamide. In a mixture of 4 - ((1S, 2S) -2-gidroksiciklopentilamino) -2- (methylthio) pyrimidine-5-carboxamide (800 mg, 2.98 mmol) in acetone (10 ml) solution of dobavlâli Potassium peroxymonosulfate (4.66 g , 7.45 mmol) in water (10 ml), and mix polučennuû peremešivali komnatnoj at temperatures in week 2 h. After rigidly substance was taken as original izrashodovano, reakcionnuû blend worked between ethyl acetate (20 ml) and water (15 ml). Water layer ékstragirovali with ethyl acetate (20 ml × 3). Émirats organic layers promyvali nasyŝennym solevym solution, dried over sodium sulphate and filʹtrovali. The filtrate under vacuum paired with receipt of 4 - ((1S, 2S) -2-gidroksiciklopentilamino) -2- (methylsulfonyl) pyrimidine-5-carboxamide (700 mg, 2.3 mmol, 78% output) in the form of a rigid substances. MS (ESI): m / z 301,⁺.

I. 2 - ((1R, 4S) -4-Etoksitsiklogeksilamino) -4 - ((1S, 2S) -2-hydroxy-cyclopentylamino) pyrimidine-5-carboxamide. A solution of 4 - ((1S, 2S) -2-gidroksitsiklopentilamino) -2- (methylsulfonyl) pyrimidine-5-carboxamide (700 mg, 2.3 mmol), (1R, 4R) -4-etoksitsiklogeksanamina (668 mg, 4 , 66 mmol) and DIEA (600 mg, 4.66 mmol) in dioxane (10 ml) was heated at 80 ° C for 15 hours. After that was cooled at room temperature, the reaction mixture was concentrated, and the solid residue was dissolved in ethyl acetate (20 mL). The organic solution was washed with water and saturated brine, dried over sodium sulfate and filtered. The filtrate was evaporated in vacuo. The solid residue was purified by preparative reverse phase HPLC (40-75% acetonitrile + 0.05% ammonium hydroxide in water, 7.5 min) to give 2 - (4-etoksitsiklogeksilamino (1R, 4S)) -4- ( (1S,¹H-ЯМР (ДМСО-d₆, 400 MHz):. Δ h / million 9,02-8,93 (m, 1H), 8.32 (d, J = 9,2 Hz, 1H), 7,60-7,51 (m, 1H ), 7.04 (d, J = 7,2 Hz, 1H), 6.88 (d, J = 7,2 Hz, 1H), 4.82 (s, 1H), 3,99-3,89 (m, 3H), 3.42 (q, J = 7,2 Hz, 2H), 3.15 (s, J = 6,0 Hz, 1H), 2,10-2,06 (m, 1H) , 1,97-1,77 (m, 5H), 1,66-1,60 (m, 2H), 1.46 (s, 1H), 1,28-1,18 (m, 5H), 1 06 (t, J = 7,2 Hz, 3H); MS (ESI): m / z 364,3 [M + 1]⁺.

Example 4: 4 - ((1R, 3S) -3-Gidroksiciklogeksilamino) -2 - ((1R, 4R) -4- (methylcarbamoyl) ciklogeksilamino) pyrimidine-5-carboxamide

<img file="00000104.jpg" he="39" wi="63" img-format="tif" img-content="undefined" />

A. Эtil-4 - ((1R, 3S) -3-gidroksitsiklogeksilamino) -2- (methylthio) pyrimidine-5-carboxylate. Эtil-4-chloro-2- (methylthio) pyrimidine-5-carboxylate (4.38 g, 18.82 mmoly) and (1S, 3R) -3-aminotsiklogeksanol (2,276 g, 19.76 mmoly; poluchennыy how described in Tetrahedron: Asymmetry 15: 2051-2056 (2004)) running and cut dobavleniem DIЭA (4.93 mL, 28.2 mmoly) rastvoryali in эtanole (75 ml) and heated to 60 ° C. Cherez 2:00 CHO-MS showed Chto Massa tselevogo product mistletoe dominiruyushtiy peak. Reaktsionnuyu smesy perestavali nagrevaty and kontsentrirovali. Sыroe substance ochishtali the column 340G SNAP Biotage (20-100% эtilatsetat in Gexto) with polucheniem эtil-4 - ((1R, 3S) -3-gidroksitsiklogeksilamino) -2- (methylthio) pyrimidine-5-carboxylate (5 g, 16 06 mmoly, 85% vыhod) in Vide Beloye penы; MS (ESI) m / z 312,1 [M + 1]⁺.

B. 4 - ((1R, 3S) -3-hydroxycyclohexylamino) -2- (methylthio) pyrimidine-5-carboxylic acid. Ethyl 4 - ((1R, 3S) -3-hydroxycyclohexylamino) -2- (methylthio) pyrimidine-5-carboxylate (5 g, 16.06 mmol) was dissolved in ethanol (50 ml) pre-addition of sodium hydroxide solution (2 M in water, 20 mL, 40.0 mmol) and stirred at room temperature. After 30 min, LC-MS showed mostly desired product mass. The reaction mixture was neutralized by adding a saturated aqueous solution of citric acid. The resulting precipitate was filtered and dried to give 4 - ((1R, 3S) -3-hydroxycyclohexylamino) -2- (methylthio) pyrimidine-5-carboxylic acid (4.5 g, 15.88 mmol, 99% yield) as a white solid;¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 13.21 (br. S., 1H), 8,44-8,54 (m, 2H), 4.74 (d, J = 3,90 Hz, 1H), 3.97 -4.12 (m, 1H), 3.56 (d, J = 3,12 Hz, 1H), 2.46 (s, 3H), 2.05-2.16 (m, 1H), 1, 84 (d, J = 10,15 Hz, 1H), 1.65-1.80 (m, 2H), 1,11-1,36 (m, 4H); MS (ESI) m / z 284,1 [M + 1]⁺.

C. 4 - ((1R, 3S) -3-Gidroksiciklogeksilamino) -2- (methylthio) pyrimidine-5-carboxamide. 4 - ((1R, 3S) -3-Gidroksiciklogeksilamino) -2- (methylthio) pyrimidine-5-karbonovuû acid (4.5 g, 15.88 mmol) and HATU (9.06 g, 23.82 mmol) rastvorâli in DMF (75 mL), ostavlâli peremešivatʹsâ for 5 min at komnatnoj temperature, and then ammonium chloride dobavlâli (4.25 g, 79 mmol) and DIEA (13.87 ml, 79 mmol). Reakcionnuû mix ostavlâli peremešivatʹ in komnatnoj temperature in the week nights. After rigidly, as ZH-MS showed the product had the target î dominiruûŝij pixels reakcionnuû blend worked between water and ethyl acetate. Before suškoj over sodium sulphate Organic layer promyvali one times nasyŝennym solevym solution, filʹtrovali and kondensirovali. After drying receive 4 - ((1R, 3S) -3-gidroksiciklogeksilamino) -2- (methylthio) pyrimidine-5-carboxamide (4.19 g, 14.84 mmol, 93% yield) as an off-white solid; MS (ESI) m / z 283,2 [M + 1]^+.

D. 4 - ((1R, 3S) -3-gidroksiciklogeksilamino) -2- (methylsulfonyl) pyrimidine-5-carboxamide. 4 - ((1R, 3S) -3-Gidroksiciklogeksilamino) -2- (methylthio) pyrimidine-5-carboxamide (302 mg, 1.070 mmol) in DCM suspendirovali (10 ml) and acetone (10 ml). Dobavlâli mCPBA (479 mg, 2,139 mmol), and mix reakcionnuû peremešivali in komnatnoj temperature. Through 90 min ZH-MS showed what weight celevogo product had dominiruûŝij pixels. Reakcionnuû mix quenched, dobavlââ 10 ml of 10% sodium thiosulfate solution to water. After peremešivaniâ for 5 minutes reakcionnuû mix worked between ethyl acetate and water. Thereafter Organic layer promyvali nasyŝennym sodium bicarbonate solution and nasyŝennym solevym solution. Émirats vodnye promyvali layers three times with ethyl acetate and then organic layers obʺedinâli, dried over sodium sulphate, and filʹtrovali kondensirovali. After drying, 4 - ((1R, 3S) -3-hydroxycyclohexylamino) -2- (methylsulfonyl) pyrimidine-5-carboxamide (259 mg, 0.824 mmol, 77% yield) as a white solid; MS (ESI) m / z 315,2 [M + 1]⁺.

E. (1R, 4R) -4-Amino-N-methylcyclohexanecarboxamide. Tert-butyl (1R, 4R) -4- (methylcarbamoyl) cyclohexylcarbamate (0.411 g, 1.603 mmol) was dissolved in DCM (5 mL), treated with TFA (5.56 mL, 72.1 mmol) and stirred at room temperature for 1 hour. The solvent was removed under vacuum and the solid residue was dissolved in acetonitrile and placed on solid phase extraction column Phenomenex Strada-XC and washed with 300 ml of acetonitrile. The title compound was released from the column using 2M ammonium in methanol. The solution containing the objective compound were reduced in vacuo to give (1R, 4R) -4-amino-N-methylcyclohexanecarboxamide (0.230 g, 1.475 mmol, 92% yield); MS (ESI) m / z 157,0 [M + 1]⁺.

F. 4 - ((1R, 3S) -3-Gidroksiciklogeksilamino) -2 - ((1R, 4R) -4- (methylcarbamoyl) ciklogeksilamino) pyrimidine-5-carboxamide. 4 - ((1R, 3S) -3-Gidroksiciklogeksilamino) -2- (methylsulfonyl) pyrimidine-5-carboxamide (0.231 g, 0.736 mmol), (1R, 4R) -4-amino-N-metilciklogeksankarboksamid (0.230 g, 1.472 mmol), DIEA (0.514 mL, 2.94 mmol) and DMSO (4 ml) and obʺedinâli nagrevali temperature to 100 ° C in 2 h week. Be dissolved in the paired ponižennom pressure, tire rastvorâli in a minimum quantity of methanol, mixed up on column with silica gel and Cleansing (0-15% methanol, Solid Ammonia, in DCM) with receipt of 4 - ((1R, 3S) -3-gidroksiciklogeksilamino) -2 - ((1 R, 4R) -4- (methylcarbamoyl) ciklogeksilamino) pyrimidine-5-carboxamide (0.106 g, 0.271 mmol, 36.9% output) in the form of white powder; MS (ESI) m / z 391.2 [M + 1]⁺; ¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 9.10 (br. S., 1H), 8.33 (s, 1H), 7.68 (br. S., 1H), 6,92-7,29 (m, 3H ), 4.67 (br. s., 1H), 3.87 (br. s., 1H), 3,41-3,71 (m, 2H), 2.55 (d, J = 4,30 Hz, 3H), 1,66-2,16 (m, 9H), 1,00-1,47 (m, 8H).

Example 5: Hydrochloride of 4 - ((1R, 3S) -3-hydroxycyclohexylamino) -2 - ((1R, 4R) -4- (methylamino) cyclohexylamino) pyrimidine-5-carboxamide

<img file="00000105.jpg" he="39" wi="58" img-format="tif" img-content="undefined" />

A. tert-Butyl (1R, 4R) -4- (5-carbamoyl-4 - ((1R, 3S) -3-hydroxycyclohexylamino) -pyrimidin-2-ylamino) cyclohexyl (methyl) carbamate. 4 - ((1R, 3S) -3-hydroxycyclohexylamino) -2- (methylsulfonyl) pyrimidine-5-carboxamide (0.397 g, 1.264 mmol; synthesis described herein), tert-butyl (1R, 4R) -4- aminotsiklogeksil- (methyl) carbamate (0.577 g, 2.53 mmol), DIEA (0.883 mL, 5.05 mmol) and DMSO (4 mL) were combined and heated at 100 ° C for 2 hours. The solvent was evaporated under reduced pressure , the residue dissolved in a minimum amount of methanol was placed on a silica gel column and purified (0-15% methanol saturated with ammonia in DCM) to give tert-butyl (1R, 4R) -4- (5-carbamoyl-4- ( (1R, 3S) -3-hydroxycyclohexyl ino) pyrimidin-2-ylamino) cyclohexyl (methyl) carbamate (0.210 g, 0.455 mmol, 36% yield) as a white powder; MS (ESI) m / z 463,3 [M + 1]⁺.

B. 4 - ((1R, 3S) -3-hydroxycyclohexylamino) -2 - ((1R, 4R) -4- (methylamino) cyclohexylamino) pyrimidine-5-carboxamide hydrochloride. Tert-butyl (1R, 4R) -4- (5-carbamoyl-4 - ((1R, 3S) -3-hydroxycyclohexylamino) -pyrimidin-2-ylamino) cyclohexyl (methyl) carbamate (0.150 g, 0.324 mmol) was dissolved in DCM (2 mL) and added dropwise TFA (2 mL, 26.9 mmol). The solution was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The solid residue was purified by preparative HPLC (5-40% acetonitrile / water, 20 mL / min) to afford the title compound as the corresponding TFA salt. Fractions containing the target compound were concentrated under reduced pressure, the solid residue was dissolved in methanol and hydrochloric acid (4N in dioxane, 3 mL). The resulting solution was concentrated under reduced pressure, procedure was repeated twice to give 4 - ((1R, 3S) -3-hydroxycyclohexylamino) -2 - ((1R, 4R) -4- (methylamino) cyclohexylamino) pyrimidine-5-carboxamide (0.063 g, 0.158 mmol, 48 7% yield). MS (ESI) m / z 363,5 [M + 1]⁺; ¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 9.94 (br. S., 1H), 8,83-9,01 (m, 1H), 8,38-8,49 (m, 2H), 8.15 (br. s., 1H), 7.64 (br. s., 1H), 3.96 (br. s., 1H), 3.69 (d, J = 13,67 Hz, 2H), 3.49 ( d, J = 11,32 Hz, 3H), 2.97 (br. s., 1H), 2.52 (br. s., 2H), 1,69-2,17 (m, 7H), 1 , 09-1,53 (m, 8H).

Example 6: 2- (4,4-Diftorciklogeksilamino) -4 - ((1R, 3S) -3-gidroksiciklogeksilamino) pyrimidine-5-carboxamide

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4 - ((1R, 3S) -3-hydroxycyclohexylamino) -2- (methylsulfonyl) pyrimidine-5-carboxamide (478 mg, 1.521 mmol; synthesis described in the present specification), 4,4-diftortsiklogeksanamina hydrochloride (522 mg, 3 04 mmol), DIEA (1.062 mL, 6.08 mmol) and DMSO (8 mL) were combined in a round bottom flask and heated at 100 ° C for 1 h. The reaction was stopped by heat and condensed in vacuo. The crude material was purified by column 100G SNAP Biotage (2-12% methanol saturated with ammonia in DCM). Peak fractions were pooled and evaporated. Then dried under high vacuum to give 2- (4,4-diftortsiklogeksilamino) -4 - ((1R, 3S) -3-hydroxycyclohexylamino) pyrimidine-5-carboxamide (325 mg, 0.880 mmol, 58%) as a slightly yellow powder ;¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8.93 (d, J = 7,42 Hz, 1H), 8.36 (s, 1H), 7.22 (br. S., 1H), 2,94-3,05 (m, 1H), 1,64-2,21 (m, 14H), 1,36-1,62 (m, 4H), 0,92-1,33 (m, 3H); MS (ESI) m / z 370,2 [M + 1]⁺.

Example 7: 4 - ((3S, 5R) -5-hydroxytetrahydro-2H-pyran-3-ylamino) -2 - ((1R, 4S) -4-metoksitsiklogeksilamino) pyrimidine-5-carboxamide, 4 - ((3R, 5S) -5-hydroxy-tetrahydro-2H-pyran-3-ylamino) -2 - ((1R, 4R) -4-metoksitsiklogeksilamino) pyrimidine-5-carboxamide, 4 - ((3S, 5S) -5-gidroksitetragidro- 2H-pyran-3-ylamino) -2 - ((1R, 4S) -4-metoksitsiklogeksilamino) pyrimidine-5-carboxamide, 4 - ((3R, 5R) -5-hydroxytetrahydro-2H-pyran-3-ylamino) - 2 - ((1R, 4R) -4-metoksitsiklogeksilamino) pyrimidine-5-carboxamide.

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A. 6-Hydroxy-2H-pyran-3 (6H) -one. Furan-2-ylmethanol (17.67 mL, 204 mmol) was dissolved in DCM (500 mL) and cooled to 0 ° C and then added in portions 3-chloroperoxybenzoic acid (68.5 g, 306 mmol). The reaction mixture was slowly warmed to room temperature for 6 hours, all the time from the solution precipitated solid precipitate of m-chlorobenzoic acid. The solution was cooled to -78 ° C for 15 min and the solids filtered. The filtrate was condensed to obtain a yellow solid. The crude material was purified by column 340G SNAP Biotage (20-100% ethyl acetate in hexane). Peak fractions were combined and evaporated to give 6-hydroxy-2H-pyran-3 (6H) -one (15.8 g, 138 mmol, 67.9% yield) as a pale yellow oil;¹Н-ЯМР (400 МГц, CDCl₃) Δ hr. / Million 6.94-7.01 (m, 1H), 6.18 (d, J = 10,93 Hz, 1H), 5,61-5,68 (m, 1H), 4, 56 (s, 1H), 4.17 (s, 1H), 3.61 (br. s., 1H).

B. 6- (tert-butyldimethylsilyloxy) -2H-pyran-3 (6H) -one. 6-hydroxy-2H-pyran-3 (6H) -one (9 g, 79 mmol) was dissolved in DCM (250 mL) was placed under a nitrogen atmosphere and cooled to -78 ° C. Then, one portion was added 2,6-lutidine (13.78 mL, 118 mmol), then slowly added tert-butyldimethylsilyl trifluoromethanesulfonate (21.74 mL, 95 mmol). The reaction mixture was allowed to slowly warm to 0 ° C for 4 hours. The reaction mixture was quenched by addition of ~ 20 mL of water. After quenching the solution became pale yellow. After transfer to razrazdelitelnuyu funnel, the organic phase was successively washed with 10% citric acid and brine. The organic layer was dried over sodium sulfate, filtered and condensed to obtain a yellow oil.¹Н-ЯМР (400 МГц, CDCl₃) Δ hr. / Million 6.87 (dd, J = 10.54, 3.12 Hz, 1H), 6.08 (d, J = 10.15 Hz, 1H), 5.53 (d, J = 3.12 Hz, 1H), 4.51 (d, J = 16,79 Hz, 1H), 4.08 (d, J = 16,79 Hz, 1H), 0.92 (s, 9H), 0 17 (s, 6H).

C. 6- (tert-butyldimethylsilyloxy) -3,6-dihydro-2H-pyran-3-ol. To a cooled (-20 ° C) solution of 6- (tert-butyldimethylsilyloxy) -2H-pyran-3 (6H) -one (9.9 g, 43.4 mmol) and cerium (III) chloride heptahydrate (16.15 g , 43.4 mmol) in methanol (173 ml) was added portionwise sodium borohydride (1.640 g, 43.4 mmol). In addition, there was intense bubbling. The mixture was then stirred for 30 minutes at -20 ° C, the reaction mixture was quenched with acetone (~ 20 mL) and stirred at room temperature for 1 hour. Most of the volatile solvents then evaporated. Brine was added and the slurry was transferred to a separatory funnel. The mixture was extracted three times with DCM (fatty emulsion formed). The combined organic layers were dried over sodium sulfate, filtered and condensed to give crude 6- (tert-butyldimethylsilyloxy) -3,¹Н-ЯМР (400 МГц, CDCl₃) Δ hr. / Million 5.95 (dd, J = 10,15, 2.34 Hz, 1H), 5.75 (d, J = 10,15 Hz, 1H), 5.25 (s, 1H) 4.15 (d, J = 9,37 Hz, 1H), 3.72-3.82 (m, 2H), 1.74 (d, J = 8,98 Hz, 1H), 0,86- 0.95 (m, 9H), 0 13 (s, 6H).

D. 6- (tert-butyldimethylsilyloxy) -3,6-dihydro-2H-pyran-3-ylacetate. To a solution of 6- (tert-butyldimethylsilyloxy) -3,6-dihydro-2H-pyran-3-ol (13.3 g, 57.7 mmol) and TEA (16.09 mL, 115 mmol) in DCM (200 ml ) dobavlâli uksusnyj angidrid (27.2 ml, 289 mmol) the mixture peremešivali komnatnoj at a temperature in within a night. Dobavlâli methanol (~ 3 ml), and the mixture peremešivali for 30 min at komnatnoj temperature, and then water and dobavlâli perenosili to razdelitelʹnuû funnel. Organic layer promyvali nasyŝennym solevym water and brine, dried over sodium sulphate, and filʹtrovali kondensirovali. Cleansing Syro substance to column 340G SNAP Biotage (0-50% ethyl acetate in Hexane) with receipt of 6- (tert-butyldimethylsilyloxy) -3,6-dihydro-2H-pyran-3-yl acetate (13.6 g, 49.9 mmol, 86% output) in the form of pale yellow oils;¹Н-ЯМР (400 МГц, CDCl₃) Δ hr. / Million 5,84-5,88 (m, 2H), 5,26-5,28 (m, 1H), 5.20-5.25 (m, 1H), 3.84 (dd , J = 6.25, 1.95 Hz, 2H), 2.08 (s, 3H), 0.91 (s, 9H), 0.13 (d, J = 1,17 Hz, 6H).

E. 3,6-dihydro-2H-pyran-3-ylacetate. 6- (tert-butyldimethylsilyloxy) -3,6-dihydro-2H-pyran-3-ylacetate (13.6 g, 49.9 mmol) was dissolved in DCM (250 mL) was placed under a nitrogen atmosphere and cooled to -30 ° C (dry ice / acetone, until the desired temperature). Slowly via syringe was added triethylsilane (15.95 mL, 100 mmol) followed by dropwise addition of boron trifluoride etherate (7.59 mL, 59.9 mmol). The reaction was maintained under a nitrogen atmosphere and heated slowly. After 1 h, the reaction mixture was quenched by addition of saturated sodium bicarbonate. After transferring to a separatory funnel, the organic layer was washed with water and saturated brine, dried over sodium sulfate, filtered and condensed. The crude material was purified by column 340G SNAP Biotage (0-80% ethyl acetate in hexane). Evaporation of pure fractions gave 3,6-dihydro-2H-pyran-3-yl acetate (5.5 g,¹Н-ЯМР (400 МГц, CDCl₃) Δ hr. / Million 5.09 (dtt, J = 5.73, 2.21, 2.21, 1.17, 1.17 Hz, 1H), 4.19-4.28 (m, 1H) , 4,04-4,15 (m, 1H), 3,89-3,98 (m, 1H), 3.76-3.84 (m, 1H), 2.10 (s, 3H).

F. 3,6-Dihydro-2H-pyran-3-ol. To a solution of 3,6-dihydro-2H-pyran-3-yl acetate (5.5 g, 38.7 mmol) in methanol (130 ml) was added 10 drops of 25% sodium methoxide in methanol. The solution was allowed to stir at room temperature. After 30 min, TLC (10% ethyl acetate in hexane; permanganate stain) showed an approximate ratio of starting material to product of 1: 1. An additional 10 drops of 25% sodium methoxide in methanol. After 30 min, TLC showed the ratio of product to starting material as a ~ 3: 1. An additional 10 drops of 25% sodium methoxide in methanol. After a further 30 minutes TLC showed complete conversion to product. Amberlist 15 was added and stirring continued for 15 minutes and then filtered. The solvent was evaporated to give 3,6-dihydro-2H-pyran-3-ol (3.8 g, 38.0 mmol, 98% yield) as a colorless oil;¹H-ЯМР (400 МГц, CDCl₃) Δ hr. / Million 5,90-6,02 (m, 2H), 4.19 (dt, J = 2,83, 1.51 Hz, 1H), 4.15 (dt, J = 2,83 , 1.51 Hz, 1H), 4.09 (q, J = 1,95 Hz, 1H), 4.05 (q, J = 1,95 Hz, 1H), 3.96-4.00 (m , 1H), 1.92 (br. s., 1H).

G. 2H-pyran-3 (6H) -one. 3,6-Dihydro-2H-pyran-3-ol (2.44 g, 24 37 mmol) was dissolved in DCM (100 mL) and cooled to 0 ° C and then slowly added Dess-Martin periodinane (10.34 g, 24.37 mmol). The reaction mixture was allowed to warm at room temperature for 5 hours. The reaction mixture was filtered through celite. After the filtrate was concentrated, the crude material was purified by column 100G SNAP Biotage (0-80% ethyl acetate in hexane) to give 2H-pyran-3 (6H) -one (2.33 g, 23.75 mmol, 97% yield) as a colorless oil;¹H-ЯМР (400 МГц, CDCl₃) Δ hr. / Million 7.07-7.17 (m, 1H), 6,15-6,25 (m, 1H), 4.39 (t, J = 2,54 Hz, 2H), 4, 19 (s, 2H).

H. Benzyl 5-oxotetrahydro-2H-pyran-3-ylcarbamate. 2H-pyran-3 (6H) -one (2.33 g, 23.75 mmol), benzyl carbamate (4.31 g, 28.5 mmol) and DCM (2.375 mL) was added to a small test tube and vigorously stirred. The thick syrup was added bismuth nitrate pentahydrate (III) (1,728 g, 3.56 mmol). The tube was capped and the reaction mixture was stirred vigorously overnight. The reaction mixture was diluted with DCM and filtered through a pad of celite. The filtrate was concentrated and purified by column 100G SNAP Biotage (10-100% ethyl acetate in hexane) to yield benzyl 5-oxotetrahydro-2H-pyran-3-ylcarbamate (4.35 g, 17.45 mmol, 73.5% yield) pale yellow oil;¹Н-ЯМР (400 МГц, CDCl₃) Δ hr. / Million 7.28-7.41 (m, 5H), 5,20-5,28 (m, 1H), 5.05-5.15 (m, 2H), 4,24-4 35 (m, 1H), 4.01-4.06 (m, 1H), 3,89-3,95 (m, 1H), 3.80-3.87 (m, 1H), 2.73 (d, J = 5,47 Hz, 1H), 2.64-2.71 (m, 1H).

I. 5-Benzyl gidroksitetragidro-2H-pyran-3-ylcarbamate. Benzyl 5-oksotetragidro-2H-pyran-3-ylcarbamate (4.35 g, 17.45 mmol) and Ceria (III) chloride geptagidrat (6.50 g, 17.45 mmol) in methanol rastvorâli (100 ml), pre cooling transfer to 0 ° C. Thereafter slowly dobavlâli borgidrid Sodium (0.660 g, 17.45 mmol). Intensivnoe puzyrenie was observed. Reakcionnuû blend ostavlâli peremešivatʹsâ at 0 ° C for 30 min, and then quenched, dobavlââ acetone (~ 3 ml), and peremešivali komnatnoj at a temperature in within a extra 30 min. Then reakcionnuû blend paired dryness. Substance worked between DCM and water, waterway layer promyvali DCM (5h). Organic layers obʺedinâli, dried over sodium sulfate, and filʹtrovali kondensirovali neočiŝennogo with receipt of benzyl 5-gidroksitetragidro-2H-pyran-3-ylcarbamate (2.5 g, 9.95 mmol, 57,¹Н-ЯМР (400 МГц, CDCl₃) Δ hr. / Million 7.28-7.39 (m, 5H), 5,90-6,06 (m, 1H), 5.10 (d, J = 4,29 Hz, 2H), 3, 59-3,97 (m, 6H), 1,77-2,06 (m, 3H); MS (ESI) m / z 252,1 [M + 1]⁺.

J. 5-aminotetrahydro-2H-pyran-3-ol. Benzyl 5-hydroxytetrahydro-2H-pyran-3-ylcarbamate (2.5 g, 9.95 mmol) was dissolved in DCM (20 ml) and methanol (20.00 mL), and then, a catalyst (10% palladium on carbon) and covered tee. The flask was discharged and flushed with hydrogen (3x) while maintaining an atmosphere of hydrogen using balloon. The reaction mixture was allowed to stir at room temperature overnight. Once material was converted completely to the product (determined by LCMS), the reaction mixture was filtered through a pad of Celite, washed thoroughly with DCM and methanol. The filtrate was concentrated to give crude 5-aminotetrahydro-2H-pyran-3-ol (1.13 g, 9.65 mmol, 97% yield) as a brown resin.¹Н-ЯМР (400 МГц, DMCO-d₆) Δ hr. / Million 4,28-4,66 (m, 2H), 3.66 (ddd, J = 10.93, 3.90, 1.56 Hz, 2H), 3.44-3.55 (m, 1H), 2,89-3,01 (m, 2H), 2.81 (s, 1H), 2.01-2.13 (m, 1H), 1.22 (d, J = 12 , 10 Hz, 1H).

C. Ethyl 2 - ((1R, 4R) -4-metoksitsiklogeksilamino) -4- (methylthio) pyrimidin-5-carboxylate. (1R, 4R) -4-metoksitsiklogeksanamin (4.39 g, 34.0 mmol), ethyl 2-chloro-4- (methylthio) pyrimidine-5-carboxylate (3.95 g, 16.98 mmol), DIEA (5.93 mL, 34.0 mmol) and 1,4-dioxane (100 ml) were combined and heated at 80 ° C overnight. The reaction mixture was cooled and condensed. The crude material was purified by Biotage (20-80% ethyl acetate in hexane) to give ethyl 2 - ((1R, 4R) -4-metoksitsiklogeksilamino) -4- (methylthio) pyrimidin-5-carboxylate (3.1 g, 9, 53 mmol, 56% yield) as a pale yellow solid;¹H-ЯМР (ДМСО-d₆, 400 MHz) δ hr. / Million 8.60 (s, 0,35N), 8.54 (s, 0,65N), 8.05 (d, J = 7,4 Hz, 0,64N) 7 87 (d, J = 8,2 Hz, 0,36N), 4.22 (q, J = 7,0 Hz, 2H), 3,69-3,90 (m, 1H), 3.23 ( s, 3H), 3.00-3.20 (m, 1H), 2.40 (s, 2H), 2.38 (s, 1H), 1,79-2,12 (m, 4H), 1 , 09-1,44 h / million (m, 7H).; MS (ESI) m / z 326,3 [M + 1]⁺.

L. 2 - ((1R, 4R) -4-Metoksiciklogeksilamino) -4- (methylthio) pyrimidin-5-karbonovaâ acid. Ethyl 2 - ((1R, 4R) -4-metoksiciklogeksilamino) -4- (methylthio) pyrimidine-5-carboxylate (3.1 g, 9.53 mmol) in rastvorâli ethanol (60 ml), and then a solution of dobavlâli Water gidroksida sodium (2 M, 23.81 mL, 47.62 mmol) and peremešivali in komnatnoj temperature. Through 30 min ZH-MS showed mainly the product celevogo fun. Reakcionnuû mix nejtralizovali, dobavlââ Solid Water solution of lemon acids. Recieved osadok filʹtrovali and dried with receipt of 2 - ((1R, 4R) -4-metoksiciklogeksilamino) -4- (methylthio) pyrimidin-5-karbonovoj acids (2.76 g, 9.28 mmol, 97% output) in the form of white Solid substances;¹Н-ЯМР (DMCO-d₆, 400 MHz) δ hr. / Million 12.59 (s, 1H), 8.57 (s, 0,38N), 8.50 (s, 0,62N), 7.94 (d, J = 7, 4Hz, 0,62N), 7.77 (d, J = 7,8 Hz, 0,38N), 3.70-3.90 (m, 1H), 3.23 (s, 3H), 3, 02-3,18 (m, 1H), 2.37 (s, 2H), 2.36 (s, 1H), 1,83-2,09 (m, 4H), 1,11-1,46 h ./mln (m, 4H); MS (ESI) m / z 298,2 [M + 1]⁺.

M. 2 - ((1R, 4R) -4-Metoksiciklogeksilamino) -4- (methylthio) pyrimidine-5-carboxamide. 2 - ((1R, 4R) -4-metoksiciklogeksilamino) -4- (methylthio) pyrimidin-5-karbonovuû acid (2.66 g, 8.94 mmol) and HATU (5.10 g, 13.42 mmol) rastvorâli in DMF (35 ml) and ostavlâli peremešivatʹsâ for 5 min at komnatnoj temperature, and then ammonium chloride dobavlâli (2.392 g, 44.7 mmol) and DIEA (7.81 ml, 44.7 mmol). Reakcionnuû blend ostavlâli peremešivatʹsâ in komnatnoj temperature for 30 min. ZH-MS showed the product as massu celevogo dominiruûŝij, reakcionnuû blend worked between water and ethyl acetate. Organic layer promyvali one times nasyŝennym solevym solution and then dried over sodium sulphate, and filʹtrovali kondensirovali. Was then dried with receipt of 2 - ((1R, 4R) -4-metoksiciklogeksilamino) -4- (methylthio) pyrimidine-5-carboxamide (2.54 g, 8.57 mmol,¹Н-ЯМР (ie ДМСО₆, 400 MHz) δ hr. / Million 8.41 (s, 1H), 7.63 (d, J = 7,0 Hz, 0,76N), 7.45 (d, J = 7,0 Hz, 0 , 24H), 7.08 (br. s., 1H), 3,66-3,85 (m, 1H), 3.23 (s, 3H), 3.11 (br. s., 1H), . 2.32 (s, 3H), 1,81-2,11 (m, 4H), 1.10-1.44 parts / million (m, 4H); MS (ESI) m / z 283,2 [M + 1]⁺.

N 2 - ((1R, 4R) -4-Metoksiciklogeksilamino) -4- (methylsulfinyl) pyrimidine-5-carboxamide. 2 - ((1R, 4R) -4-Metoksiciklogeksilamino) -4- (methylthio) pyrimidine-5-carboxamide (3 g, 10.12 mmol) in rastvorâli NMP (30 ml). Thereafter, at 0 ° C Porcia dobavlâli mCPBA (2.268 g, 10.12 mmol), and reakcionnuû peremešivali mix, slowly povyšaâ temperature reactions to komnatnoj temperature. Through 30 min reakcionnuû blend razbavlâli water (200 ml), peremešivali for 10 min, and a substance obtained by tverdoe udalâli via filtration. The filtrate under vacuum koncentrirovali with receipt of 2 - ((1R, 4R) -4-metoksiciklogeksilamino) -4- (methylsulfinyl) pyrimidine-5-carboxamide in the form of a translucent, pale-yellow solution in NMP (~ 25 ml). This crude product ispolʹzovali in next Stages at no extra cleaning. MS (ESI) m / z 313.3 [M + 1]⁺.

ABOUT. 4 - ((3S, 5R) -5-Gidroksitetragidro-2H-pyran-3-ylamino) -2 - ((1R, 4S) -4-metoksiciklogeksilamino) pyrimidine-5-carboxamide, 4 - ((3R, 5S) - 5-gidroksitetragidro-2H-pyran-3-ylamino) -2 - ((1R, 4R) -4-metoksiciklogeksilamino) pyrimidine-5-carboxamide, 4 - ((3S, 5S) -5-gidroksitetragidro-2H-pyran-3 ylamino) -2 - ((1R, 4S) -4-metoksiciklogeksilamino) pyrimidine-5-carboxamide, 4 - ((3R, 5R) -5-gidroksitetragidro-2H-pyran-3-ylamino) -2 - ((1 R , 4R) -4-metoksiciklogeksilamino) pyrimidine-5-carboxamide. To 2 - ((1R, 4R) -4-metoksiciklogeksilamino) -4- (methylsulfinyl) pyrimidine-5-carboxamide (3.1 g, 9.92 mmol) in NMP (25 ml)) of crude 5-dobavlâli aminotetragidro-2N pyran-3-ol (1.15 g, 9.82 mmol) in NMP in the quality of the solution (20 ml). To suspensions dobavlâli DIEA (8.57 ml, 49.1 mmol), and reakcionnuû nagrevali blend to 100 ° C in the night a week. The most of NMP udalâli uparivaniem at 70 ° C, the solid residue was diluted with DCM and purified on 340G SNAP Biotage column chromatography (0-15% methanol in DCM over 2000 ml). The product fractions were combined and concentrated to give 2.8 g (78%) of material which had a purity of ~ 85%. The material was dissolved in DCM and repurified on 340G SNAP Biotage column chromatography (2-15% methanol saturated with ammonia in dichloromethane). The product fractions were combined and concentrated to give a mixture of four products (two diastereomers and their respective enantiomers; 1.95 g),&gt; 99% purity. The crude material was isolated by chiral SFC, using AD-H column to afford 4 designated PIC-1 PIC 4, PIC where 1 was the first compound eluted and PIC 4 was the last eluted compound. The product fractions were combined and concentrated to give 2.8 g (78%) of material which had a purity of ~ 85%. The material was dissolved in DCM and repurified on 340G SNAP Biotage column chromatography (2-15% methanol saturated with ammonia in dichloromethane). The product fractions were combined and concentrated to give a mixture of four products (two diastereomers and their respective enantiomers; 1.95 g),&gt; 99% purity. The crude material was isolated by chiral SFC, using AD-H column to afford 4 designated PIC-1 PIC 4, PIC where 1 was the first compound eluted and PIC 4 was the last eluted compound. The product fractions were combined and concentrated to give 2.8 g (78%) of material which had a purity of ~ 85%. The material was dissolved in DCM and repurified on 340G SNAP Biotage column chromatography (2-15% methanol saturated with ammonia in dichloromethane). The product fractions were combined and concentrated to give a mixture of four products (two diastereomers and their respective enantiomers; 1.95 g),&gt; 99% purity. The crude material was isolated by chiral SFC, using AD-H column to afford 4 designated PIC-1 PIC 4, PIC where 1 was the first compound eluted and PIC 4 was the last eluted compound. The product fractions were combined and concentrated to give a mixture of four products (two diastereomers and their respective enantiomers; 1.95 g),&gt; 99% purity. The crude material was isolated by chiral SFC, using AD-H column to afford 4 designated PIC-1 PIC 4, PIC where 1 was the first compound eluted and PIC 4 was the last eluted compound. The product fractions were combined and concentrated to give a mixture of four products (two diastereomers and their respective enantiomers; 1.95 g),&gt; 99% purity. The crude material was isolated by chiral SFC, using AD-H column to afford 4 designated PIC-1 PIC 4, PIC where 1 was the first compound eluted and PIC 4 was the last eluted compound.

Peak 1: ¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8.41 (s, 1H), 4.38 (br. S., 1H), 3,53-3,79 (m, 4H), 3.24 (s, 3H), 2 , 87-2,98 (m, 3H), 1,89-2,07 (m, 4H), 1.65-1.78 (m, 1H), 1.19-1.43 (m, 4H) ; MS (ESI) m / z 366,3 [M + 1]⁺.

Pic 2: ¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8,86-9,01 (m, 1H), 8.35 (br. S., 1H), 6,91-7,18 (m, 1H), 4,91-4,99 ( m, 1H), 3,49-4,13 (m, 4H), 3.23 (s, 3H), 2.85-3.15 (m, 3H), 1,79-2,28 (m, 5H), 1,08-1,41 (m, 5H), 1.04 (d, J = 6,25 Hz, 1H); MS (ESI) m / z 366,3 [M + 1]⁺.

Pic 3: ¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8,86-9,02 (m, 1H), 8,32-8,40 (m, 1H), 6,88-7,20 (m, 1H), 4,91-5 00 (m, 1H), 3,49-4,15 (m, 5H), 3.22 (s, 3H), 2,79-3,14 (m, 3H), 1.82 (s, 5H ), 1.12 (t, J = 7,22 Hz, 6H); MS (ESI) m / z 366,3 [M + 1]⁺.

Pic 4: ¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8,99-9,24 (m, 1H), 8.36 (br. S., 1H), 6,79-7,20 (m, 2H), 4,72-4,94 ( m, 1H), 4,17-4,46 (m, 1H), 3,43-3,77 (m, 4H), 3.23 (s, 4H), 3.03-3.13 (m, 1H), 2.73 (s, 1H), 1.98 (br s, 6H), 1,03-1,35 (m, 5H)..; MS (ESI) m / z 366,3 [M + 1]⁺.

Example 8: 4- (3-Gidroksi-3-butylamino) -2 - ((1R, 4R) -4-metoksitsiklogeksilamino) pyrimidine-5-carboxamide

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A. 2 - ((1R, 4R) -4-Metoksitsiklogeksilamino) -4- (methylsulfinyl) pyrimidine-5-carboxamide. To a stirred colorless solution of 2 - ((1R, 4R) -4-metoksitsiklogeksilamino) -4- (methylthio) pyrimidine-5-carboxamide (0.200 g, 0.675 mmol; synthesis described herein) in NMP (2 mL) was added mCPBA in portions (0.151 g, 0.675 mmol) at 0 ° C. The reaction mixture was stirred at room temperature for 2 h before the readings on LC-MS the reaction was complete. The reaction mixture was diluted with water (20 ml) and filtered. The filtrate was concentrated to give 2 - ((1R, 4R) -4-metoksitsiklogeksilamino) -4- (methylsulfinyl) pyrimidine-5-carboxamide (0.211 g, 100% yield) as a white sticky solid which was used in the next step without further cleaning. MS (ESI) m / z 313,1 [M + 1]⁺.

B. 4- (3-Hydroxy-3-methylbutylamino) -2 - ((1R, 4R) -4-metoksitsiklogeksilamino) pyrimidine-5-carboxamide. To a solution of 2 - ((1R, 4R) -4-metoksitsiklogeksilamino) -4- (methylsulfinyl) pyrimidine-5-carboxamide (0.211 g, 0.675 mmol) and DIEA (0.236 mL, 1.351 mmol) in NMP (2 mL) was added 4 amino-2-methylbutan-2-ol (0.105 g, 1.013 mmol) at room temperature. The reaction mixture was stirred for 2 hours at 70 ° C. After completion of the reaction by indications LCMS and TLC, the reaction mixture was concentrated and purified by silica gel chromatography (0% -15% methanol saturated with ammonia in DCM). The product fractions were combined and concentrated to give 4- (3-hydroxy-3-methylbutylamino) -2 - ((1R, 4R) -4-metoksitsiklogeksilamino) pyrimidine-5-carboxamide (0.143 g, 60.2% yield, 95.8 % pure) as a light yellow solid.¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8,81-9,03 (m, 1H), 8.32 (s, 1H), 6,75-7,06 (m, 2H), 4.28 (s, 1H) 3,63-3,77 (m, 1H), 3.39-3.52 (m, 2H), 3.22 (s, 3H), 3.02-3.11 (m, 1H), 1, 81-2,06 (m, 4H), 1.57-1.67 (m, 2H), 1,21-1,34 (m, 2H), 1.16 (br. s., 1 H), 1 13 (s, 8H). MS (ESI) m / z 352,4 [M + 1]⁺.

Example 9: 4 - ((1R, 2S) -2- (Gidroksimetil) cyclopentylamino) -2 - ((1R, 4R) -4-metoksiciklogeksilamino) pyrimidine-5-carboxamide, 4 - ((1S, 2R) -2- (gidroksimetil) cyclopentylamino) -2 - ((1R, 4S) -4-metoksiciklogeksilamino) pyrimidine-5-carboxamide

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A. Ethyl-4- (cis-2- (hydroxymethyl) cyclopentylamino) -2- (methylthio) pyrimidine-5-carboxylate. To a stirred solution of ethyl 4-chloro-2- (methylthio) pyrimidine-5-carboxylate (5.00 g, 21.49 mmol) and cis- (2-aminocyclopentyl) methanol (2.60 g, 22.56 mmol) in ethanol (85 mL) was added DIEA (5.61 mL, 32.2 mmol) and heated to 60 ° C for 2.5 hours. After completion of reaction indications LCMS and TLC, the reaction mixture was cooled and concentrated, then purified by chromatography on silica gel (0-80% ethyl acetate / hexane). Appropriate fractions were combined and concentrated to give ethyl-4- (cis-2- (hydroxymethyl) cyclopentylamino) -2- (methylthio) pyrimidine-5-carboxylate (6.4 g, 96% yield) as a white solid. MS (ESI) m / z 312,4 [M + 1]⁺.

B. 4- (cis-2- (hydroxymethyl) cyclopentylamino) -2- (methylthio) pyrimidine-5-carboxylic acid. To a stirred solution of ethyl 4- (cis-2- (hydroxylmethyl) cyclopentylamino) -2- (methylthio) pyrimidine-5-carboxylate (6.4 g, 20.55 mmol) in ethanol (100 ml) was added aqueous sodium hydroxide (1 M, 51.4 mL, 51.4 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After completion of reaction indications LCMS and TLC, the reaction mixture was concentrated, diluted with water (100 ml), then neutralized by stirring with aqueous citric acid (2 M, 51.4 mL, 103 mmol). The resulting precipitate was filtered, washed with water (2 × 50 mL) and dried to give 4- (cis-2- (hydroxymethyl) cyclopentylamino) -2- (methylthio) pyrimidine-5-carboxylic acid (5.6 g, 96% yield) as a white solid.¹Н-ЯМР (400 МГц, DMCO-d₆) Δ hr. / Million 13.17 (br. S., 1H), 8.71 (d, J = 7,42 Hz, 1H), 8.50 (s, 1H), 4,49-4,60 (m, 2H), 3.40-3.46 (m, 1H), 3.32-3.39 (m, 2H), 2.47 (s, 3H), 2.22 (skst., J = 6.87 Hz, 1H), 1.95-2.04 (m, 1H), 1.78 (qd, J = 4.49, 8.00 Hz, 1H), 1,66-1,72 (m , 1H), 1.49-1.61 (m, 2H). MS (ESI) m / z 284,3 [M + 1]⁺.

C. 4- (cis-2- (hydroxymethyl) cyclopentylamino) -2- (methylthio) pyrimidine-5-carboxamide. The white suspension of 4- (cis-2- (hydroxymethyl) cyclopentylamino) -2- (methylthio) pyrimidine-5-carboxylic acid (5.6 g, 19.76 mmol) and HATU (11,27 g, 29,60 mmol) was dissolved in DMF (79 ml) and stirred for 5 minutes at room temperature and then added ammonium chloride (5.29 g, 99 mmol) and DIEA (17.26 ml, 99 mmol). The reaction mixture was stirred at room temperature for 1 h, then diluted with water (200 mL) and extracted with ethyl acetate (2 × 200 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated. The residual amount of the DMF was removed by suspending the white suspension in 200 ml of water and 200 ml of hexane. The biphasic mixture was stirred vigorously for 30 min, filtered and washed with hexane to give 4- (cis-2- (hydroxylmethyl) cyclopentylamino) -2- (methylthio) pyrimidine-5-carboxamide (4.50 g, 81% yield) as a white solid. MS (ESI) m / z 283,4 [M + 1]⁺.

D. 4- (cis-2- (hydroxymethyl) cyclopentylamino) -2- (methylsulfonyl) pyrimidine-5-carboxamide. To a stirred suspension of 4- (cis-2- (hydroxymethyl) -tsiklopentilamino) -2- (methylthio) pyrimidine-5-carboxamide (3.5 g, 12.40 mmol) in DCM (62 ml) and acetone (62 ml) was added mCPBA (5,56 g, 24.79 mmol) and stirred at room temperature for 1.5 hours. The crude reaction mixture was quenched by adding 75 ml of 10% aqueous sodium thiosulfate, stirred for 5 minutes and then evaporated greater of the volatile solvents. The substance was partitioned between ethyl acetate (200 mL) and water (200 ml) and the combined organic layers were washed with saturated sodium bicarbonate solution and then brine. The combined aqueous layers were then washed with ethyl acetate (3x), the organic layers were combined, dried over sodium sulfate, filtered and condensed. After drying under high vacuum yielded 4- (cis-2- (hydroxymethyl) cyclopentylamino) -2- (methylsulfonyl) pyrimidine-5-carboxamide (1.2 g, 3.82 mmol, 30.8% yield) as a substance belogotverdogo . MS (ESI) m / z 315,2 [M + 1]⁺.

E. 4 - ((1R, 2S) -2- (Gidroksimetil) cyclopentylamino) -2 - ((1R, 4R) -4-metoksiciklogeksilamino) pyrimidine-5-carboxamide, 4 - ((1S, 2R) -2- (gidroksimetil) cyclopentylamino) -2 - ((1R, 4S) -4-metoksiciklogeksilamino) pyrimidine-5-carboxamide. To peremešannoj suspensions of 4- (cis-2- (gidroksimetil) cyclopentylamino) -2- (methylsulfonyl) pyrimidine-5-carboxamide (1.2 g, 3.82 mmol) and hydrochloride (1 R, 4R) -4-metoksiciklogeksanamina (1 , 90 g, 11.46 mmol) in dioxane (40 ml) dobavlâli DIEA (4 ml, 22.92 mmol) and a solution of peremešivali recieved at 100 ° C within the next 48 h. Syru reakcionnuû koncentrirovali mix, and thereafter Cleansing via chromatography on silica gel (0% -15% methanol, Solid Ammonia, in DCM). Product fractions were zagrâzneny, and the target product and osaždali filʹtrovali from Emirats fractions using DCM, methanol, and water with receipt Connection, of the title compound as a mixture of two enantiomers (0.420 g, 30.3% yield) as a white solid. The crude material is separated on chiral SFC, using AD-H column to afford 2 compounds, designated as peak 1 and peak 2, where peak 1 was first eluted compound, and PIC 2 - second eluted compound.

PIC 1. ¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 9,04-9,21 (m, 1H), 8,31-8,39 (m, 1H), 6,87-7,12 (m, 2H), 4,33-4 46 (m, 2H), 3,57-3,80 (m, 1H), 3.35-3.44 (m, 1H), 3,25-3,31 (m, 1H), 3.23 (s, 3H), 3.08 (t, J = 8,20 Hz, 1H), 2.09-2.23 (m, 1H), 2.00 (d, J = 11,71 Hz, 2H) , 1.80-1.94 (m, 3H), 1.63-1.78 (m, 2H), 1.50-1.61 (m, 2H), 1.44 (br. s., 1H ), 1,09-1,33 (m, 5H); MS (ESI) m / z 364,5 [M + 1]⁺.

PIC 2. ¹Н-ЯМР (400 МГц, DMCO-d₆) Δ hr. / Million 9,03-9,18 (m, 1H), 8.34 (br. S., 1H), 6,87-7,11 (m, 2H), 4,32-4, 48 (m, 2H), 3,58-3,77 (m, 1H), 3.35-3.45 (m, 1H), 3.28 (dd, J = 7.03, 10.15 Hz, 1H), 3.22 (s, 3H), 3.03-3.13 (m, 1H), 2.09-2.25 (m, 1H), 2.00 (d, J = 8,59 Hz , 2H), 1.81-1.95 (m, 3H), 1.63-1.77 (m, 2H), 1.51-1.60 (m, 2H), 1.37-1.47 (m, 1H), 1,09-1,33 (m, 5H); MS (ESI) m / z 364,5 [M + 1]⁺.

Example 10: 4 - ((1R, 3R) -3-Gidroksi-3-metiltsiklogeksilamino) -2 - ((1R, 4R) -4-metoksitsiklogeksilamino) pyrimidine-5-carboxamide, 4 - ((1R, 3S) -3 -gidroksi-3-metiltsiklogeksilamino) -2 - ((1R, 4R) -4-metoksitsiklogeksilamino) pyrimidine-5-carboxamide

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A. (1S, 3R) -3- (Dibenzylamino) cyclohexanol. To a suspension of (1S, 3R) -3-aminocyclohexanol (5 g, 43.4 mmol; prepared as described in Tetrahedron: Asymmetry 15: 2051-2056 (2004)) and sodium bicarbonate (12.03 g, 143 mmol) in ethanol (100 mL) was added (chloromethyl) benzene (15.01 mL, 130 mmol) at room temperature. The reaction mixture was heated to 75 ° C overnight. After completion of the reaction by indications LCMS and TLC, the reaction mixture was filtered and the filtrate was concentrated. The precipitate was then dissolved in DCM (250 mL) and washed with aqueous sodium hydroxide (1 N, 2 × 100 ml) and saturated brine (1 × 100 mL). The combined organic layers were dried over anhydrous magnesium sulfate, concentrated and purified by silica gel chromatography (0% -80% ethyl acetate in hexane) to yield (1S, 3R) -3- (dibenzylamino) cyclohexanol (11.70 g,¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 7.26-7.37 (m, 8H), 7.17-7.22 (m, 2H), 4.56 (d, J = 4,30 Hz, 1H), 3, 57 (s, 4H), 3.16-3.26 (m, 1H), 2.41 (tt, J = 3.17, 11.86 Hz, 1H), 1.99-2.06 (m, 1H), 1.72 (d, J = 8,20 Hz, 2H), 1.63-1.69 (m, 1H), 1.18-1.28 (m, 2H), 0.98 (t , 2H); MS (ESI) m / z 296,4 [M + 1]⁺.

B. (R) -3- (Dibenzylamino) cyclohexanone. Oxalyl chloride (2.70 mL, 30.9 mmol) was dissolved in dry DCM (150 mL) and cooled to -78 ° C. The reaction mixture was added dropwise DMSO (4.78 mL, 67.3 mmol) in dry DCM (20 ml) and the reaction mixture was stirred for 15 min at -78 ° C. We were then added dropwise (1S, 3R) -3- (dibenzylamino) cyclohexanol (8.287 g, 28.1 mmol) in dry DCM (100 ml) using an addition funnel and the reaction mixture was stirred at -78 ° C for 15 min . Was added TEA (19.55 ml, 140 mmol) and the reaction mixture was stirred at -78 ° C for 1 hour. The ice bath was removed from the dry and the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was washed with saturated brine (100 ml), the organic layer was separated, dried over magnesium sulfate and concentrated. By slow addition of diethyl ether to the residue, impurities were precipitated, and was removed by filtration. Addition of diethyl ether to the filtrate gave (R) -3- (dibenzylamino) cyclohexanone (6.05 g, 74%) as a white solid which was collected by filtration and dried.¹H-NMR (400 MHz, DMSO-d₆) Δ h. / M 7,26-7,39 (m, 8N), 7,17-7,25 (m, 2H), 3,56-3,70 (m, 4H), 2,71-2 81 (m, 1 H), 2,60-2,69 (m, 1H), 2,25-2,42 (m, 2H), 2,04-2,11 (m, 1H), 1.88 -1.99 (m, 2H), 1,69-1,82 (m, 1H), 1,18-1,33 (m, 1H); MS (ESI) m / z 294,4 [M + 1]⁺.

C. (3R) -3- (dibenzylamino) -1-methylcyclohexanol. To a clear colorless solution of (R) -3- (dibenzylamino) cyclohexanone (5.697 g, 19.42 mmol) in dry diethyl ether (300 mL) was cautiously added dropwise a solution of 3 M of methylmagnesium bromide (8.09 ml, 24.27 mmol ) at 0 ° C. The reaction mixture was stirred at 0 ° C for 15 minutes and then the ice bath was removed. The reaction mixture was stirred at room temperature for 2 hours. After completion of reaction indications LCMS and TLC turbid solution was carefully poured into saturated aqueous ammonium chloride solution (250 mL). The ether layer was separated, and the aqueous layer was re-extracted with ether (250 mL). The combined ether layers were dried over magnesium sulfate, concentrated and purified by silica gel chromatography (0% -80% ethyl acetate in hexane) to give two diastereomeric isomers of (3R) -3- (dibenzylamino) -1-methylcyclohexanol (isomer 1 and isomer 2) . Isomer 1 (2.704 g, 45%) was obtained as a white solid and isomer 2 (1.866 g, 31%) as a colorless oil which still contained a small amount of impurities. Isomer 2 was used in the next step without further purification.

Isomer 1: ¹Н-ЯМР (400 МГц, DMCO-d₆) Δ hr. / Million 7.25-7.36 (m, 8H), 7.15-7.21 (m, 2H), 3.85 (s, 1H), 3.55 (s, 4H), 2.86 (tt, J = 3.37, 12.06 Hz, 1H), 1.70-1.81 (m, 2H), 1.38-1.49 (m, 3H), 1.32 ( t, J = 12,30 Hz, 1H), 1,15-1,27 (m, 2H), 1.12 (s, 3H); MS (ESI) m / z 310,4 [M + 1]⁺.

Изомер 2: МС (ESI) m/z 310,4 [М+1]⁺.

D. (3R) -3-Amino-1-methylcyclohexanol. A solution of isomer 1 (2.704 g, 8.74 mmol) in ethanol (50 ml) was treated with palladium hydroxide on carbon and stirred under balloon filled with hydrogen gas overnight. After completion of the reaction by LC-MS and TLC, the reaction mixture was filtered through a pad of celite and the filtrate concentrated to yield a diastereomeric isomer of (3R) -3-amino-1-methylcyclohexanol (isomer 3, 0.856 g, 76%) as a thick yellow oil. Isomer 3:¹Н-ЯМР (400 МГц, DMCO-d₆) Δ hr. / Million 3.91 (br. S., 1H), 2.73-2.84 (m, 1H), 1.61-1.72 (m, 2H), 1.54 (tt, J = 3.66, 13.13 Hz, 1H), 1.34-1.47 (m, 2H), 1,01-1,13 (m, 4H), 0.86-0.93 (m, 1H), 0,74-0,85 (m, 1H); MS (ESI) m / z 130,2 [M + 1]⁺.

The same procedure as described above, using isomer 2 (1.823 g, 5.89 mmol) in ethanol (25 ml) was used to obtain another diastereomeric isomer (3R) -3-amino-1-methylcyclohexanol (isomer 4, 0.162 g of , 21%) containing a small amount of impurities. Isomer 4 was used without further purification in the next step.

E. 2 - ((1R, 4R) -4-Metoksitsiklogeksilamino) -4- (methylsulfinyl) pyrimidine-5-carboxamide. To a stirred colorless solution of 2 - ((1R, 4R) -4-metoksitsiklogeksilamino) -4- (methylthio) pyrimidine-5-carboxamide (0.250 g, 0.843 mmol; synthesis described herein) in NMP (2 ml) was portionwise added mCPBA (0.189 g, 0.843 mmol) at 0 ° C. The reaction mixture was then stirred at room temperature for 2 h according to LC-MS the reaction was complete. The reaction mixture was diluted with water (20 ml) and filtered. The filtrate was concentrated to give 2 - ((1R, 4R) -4-metoksitsiklogeksilamino) -4- (methylsulfinyl) pyrimidine-5-carboxamide (0.263 g, 100% yield) as a white sticky solid which was used in the next step without further cleaning. MS (ESI) m / z 313,1 [M + 1]⁺.

F. 4 - ((1R, 3R) -3-Gidroksi-3-metiltsiklogeksilamino) -2 - ((1R, 4R) -4-metoksitsiklogeksilamino) pyrimidine-5-carboxamide, 4 - ((1R, 3S) -3- Gidroksi-3-metiltsiklogeksilamino) -2 - ((1R, 4R) -4-metoksitsiklogeksilamino) pyrimidine-5-carboxamide. K rastvoru 2 - ((1R, 4R) -4-metoksitsiklogeksilamino) -4- (metilsulyfinil) pyrimidine-5-carboxamide (0.263 g, 0.842 mmoly) and DIЭA (0.294 ml, 1,684 mmoly) in NMP (3 mL) dobavlyali isomer 3 (0.163 g, 1,263 mmoly) at komnatnoy temperature. Reaktsionnuyu smesy peremeshivali over 2 h at 70 ° C. Then due and payable reactions dannыm CHO-MS and TLC reaktsionnuyu smesy kontsentrirovali and ochishtali with pomoshtyyu chromatographies on silica gel (0% to 20% methanol nasыshtennыy ammiakom in DCM). Fractions product obaedinyali and kontsentrirovali with polucheniem odnogo diastereomernogo isomer 4 - ((1R) -3-gidroksi-3-metiltsiklogeksilamino) -2 - ((1R, 4R) -4-metoksitsiklogeksilamino) pyrimidine-5-carboxamide (Isomer 5, 0.265 g, 83% yield) as a white solid. Isomer 5:¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8.79 (d, J = 7,42 Hz, 1H), 8.32 (s, 1H), 6,76-7,05 (m, 2H), 4,12-4, 32 (m, 1H), 4.07 (s, 1H), 3,57-3,82 (m, 1H), 3.23 (s, 3H), 3.04-3.16 (m, 1H) , 1.81-2.05 (m, 6H), 1.60-1.74 (m, 2H), 1.42-1.54 (m, 2H), 1.15-1.35 (m, 6H), 1.12 (s, 4H); MS (ESI) m / z 378,5 [M + 1]⁺.

The same facials uru as described above using Isomer 4 (0.163 g, 1.263 mmol), 2 - ((1R, 4R) -4 - metoksitsiklogeksilamino) -4- (methylsulfinyl) pyrimidine-5-carboxamide (0.263 g, 0.842 mmol) and DIEA (0.294 mL, 1.684 mmol) in NMP (3 ml) was used to obtain another isomer of diastereomeric 4 - ((1R) -3-hydroxy-3-methylcyclohexylamine) -2 - ((1R, 4R ) -4 -metoksitsiklogeksilamino) pyrimidine-5-carboxamide (isomer 6, 0.043 g, 14% yield) as a white solid. Isomer 6:¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8.99 (d, J = 4,69 Hz, 1H), 8.32 (s, 1H), 6,69-7,08 (m, 2H), 4.45 (s, 1H), 3,95-4,13 (m, 1H), 3,59-3,71 (m, 1H), 3.22 (s, 3H), 3.04-3.16 (m, 1H) , 1,86-2,05 (m, 5H), 1.62-1.83 (m, 2H), 1.43-1.57 (m, 1H), 1.23-1.40 (m, 5H), 1,09-1,21 (m, 7H); MS (ESI) m / z 378,5 [M + 1]⁺.

The stereochemistry of the individual isomers can be determined after repeating the synthesis using (1S, 3R) -3-amino-1-methylcyclohexanol (prepared as described herein), which gave isomer 6, namely 4 - ((1R, 3S) - 3-hydroxy-3-methylcyclohexylamine) -2 - ((1R, 4R) -4-metoksitsiklogeksilamino) pyrimidine-5-carboxamide. Therefore isomer 5 was a 4 - ((1R, 3R) -3-hydroxy-3-methylcyclohexylamine) -2 - ((1R, 4R) -4-metoksitsiklogeksilamino) pyrimidine-5-carboxamide.

Example 11: 2 - ((1R, 4R) -4-Atsetamidotsiklogeksilamino) -4 - ((1R, 3S) -3-gidroksitsiklogeksilamino) pyrimidine-5-carboxamide

<img file="00000111.jpg" he="39" wi="64" img-format="tif" img-content="undefined" />

A. tert-Butyl (1R, 4R) -4-atsetamidotsiklogeksilkarbamat. To a stirred solution of tert-butyl (1R, 4R) -4-aminocyclohexylcarbamate (1.0 g, 4.67 mmol) in ethyl acetate (30 ml) was added in one portion acetic anhydride (0.485 mL, 5.13 mmol). The resulting mixture was allowed to stir overnight at room temperature. To the mixture was added an additional portion of acetic anhydride (0.162 mL, 1.71 mmol) and the mixture was continued stirring for another hour at room temperature. The reaction mixture was then diluted with an additional portion of ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate (50 ml) and saturated aqueous sodium chloride solution (50 mL). The aqueous layers were combined and extracted with 50 ml of ethyl acetate. The combined ethyl acetate layers were dried over anhydrous magnesium sulfate,¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 7.66-7.74 (m, 1H), 6,67-6,77 (m, 1H), 3.40 (d, J = 7,42 Hz, 1H), 3, 11-3,22 (m, 1H), 1.65-1.82 (m, 7H), 1.37 (s, 9H), 1.16 (d, J = 8,20 Hz, 4H). MS (ESI) m / z 201,2 [M-tBu]⁺.

B. N - ((1R, 4R) -4-Aminocyclohexyl) acetamide 2,2,2-trifluoroacetate. To a stirred solution of tert-butyl (1R, 4R) -4-atsetamidotsiklogeksilkarbamata (1.04 g, 4.06 mmol) in DCM (25 mL) in one portion was added TFA (25 mL). The resulting mixture was allowed to stir at room temperature for 90 min. The reaction mixture was concentrated to dryness. The resulting oil was triturated with diethyl ether to obtain solids which were filtered, washed with additional diethyl ether and then dried in vacuo to yield N - ((1R, 4R) -4-aminocyclohexyl) acetamide 2,2,2-trifluoroacetate ( 1.07 g, 3.96 mmol, 98% yield) which was used without further purification.¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 7.82 (br. S., 3H), 3.42 (ddd, J = 15.42, 7.61, 3.90 Hz, 1H), 2,89-3,04 ( m, 1H), 1.87-1.95 (m, 2H), 1.78-1.85 (m, 2H), 1.77 (s, 3H), 1.29-1.42 (m, 2H), 1,11-1,25 (m, 2H). MS (ESI) m / z 157,0 [M + 1]⁺.

C. 2 - ((1R, 4R) -4-atsetamidotsiklogeksilamino) -4 - ((1R, 3S) -3-hydroxycyclohexylamino) pyrimidine-5-carboxamide. To a stirred solution of 4 - ((1R, 3S) -3-hydroxycyclohexylamino) -2- (methylsulfonyl) pyrimidine-5-carboxamide (190 mg, 0.604 mmol; synthesis described herein) and N - ((1R, 4R) - 4-amino-cyclohexyl) acetamide 2,2,2-trifluoroacetate (245 mg, 0.907 mmol) in DMSO (3 mL) was added DIEA (0.317 mL, 1.813 mmol). The resulting mixture was stirred at 100 ° C overnight. The crude reaction mixture was concentrated and then purified by silica gel chromatography (0-15% methanol in DCM). The product fractions were combined and concentrated to give 2 - ((1R, 4R) -4-atsetamidotsiklogeksilamino) -4 - ((1R, 3S) -3-hydroxycyclohexylamino) pyrimidine-5-carboxamide (102 mg, 0.261 mmol, 43.2% yield) as a solid.¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8.29 (s, 1H), 7.69 (d, J = 7,81 Hz, 1H), 4.60 (br. S., 1H), 3,36-3,62 (m, 2H), 2.00-2.17 (m, 1H), 1,60-1,97 (m, 10H), 0,93-1,35 (m, 10H). MS (ESI) m / z 391,2 [M + 1]⁺.

Example 12A: 4 - ((1R, 3S) -3-Gidroksiciklogeptilamino) -2 - ((1R, 4R) -4-metoksiciklogeksilamino) pyrimidine-5-carboxamide, 4 - ((1R, 3R) -3-gidroksiciklogeptilamino) - 2 - ((1R, 4R) -4-metoksiciklogeksilamino) pyrimidine-5-carboxamide, 4 - ((1S, 3R) -3-gidroksiciklogeptilamino) -2 - ((1R, 4S) -4-metoksiciklogeksilamino) pyrimidin-5- carboxamide, 4 - ((1S, 3S) -3-gidroksiciklogeptilamino) -2 - ((1R, 4S) -4-metoksiciklogeksilamino) pyrimidine-5-carboxamide

<img file="00000112.jpg" he="76" wi="108" img-format="tif" img-content="undefined" />

A. Tert-butyl-3-oksotsiklogeptilkarbamat. To a stirred mixture -cyclohept-2-enone (26.96 g, 245.0 mmol) and t-butylcarbamate (28.7 g, 245 mmol) in DCM (245 mL) was added bismuth nitrate pentahydrate (22.79 g, 47, 0 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (500 ml) and water (300 ml) and the biphasic mixture was filtered through a pad of celite. Pad of Celite, washed thoroughly with ethyl acetate and water, and the filtrate layers separated. The organic layer was concentrated to an oil which was purified by silica gel chromatography (0-40% ethyl acetate in hexane). Fractions containing product were concentrated to give compound the title compound (31.09 g, 137 mmol, 55.9% yield).¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 6.92 (d, J = 7,03 Hz, 1 H), 3.60 (d, J = 8,59 Hz, 1H), 2,55-2,69 (m, 1H ), 2,26-2,45 (m, 2H), 1,69-1,93 (m, 3H), 1.44-1.61 (m, 2H), 1.37 (d, J = 5 , 08 Hz, 11H). MS (ESI) m / z 228,5 [M + H]⁺.

B. tert-Butyl (1R, 3S) -3-gidroksitsiklogeptilkarbamat, tert-butyl (1R, 3R) -3-gidroksitsiklogeptilkarbamat, tert-butyl (1S, 3S) -3-gidroksitsiklogeptilkarbamat, tert-butyl (1S , 3R) -3-gidroksitsiklogeptilkarbamat. To a solution of tert-butyl-3-oksotsiklogeptilkarbamata (31.09 g, 137 mmol) in methanol (454 ml) was added portionwise sodium borohydride (15.52 g, 410 mmol) over ~ 10 minutes while stirring. The resulting solution was stirred for 2 hours at room temperature and then diluted with water (200 mL). The methanol was removed in vacuo and the resulting aqueous mixture was diluted with 500 mL of ethyl acetate and 100 ml of saturated aqueous sodium bicarbonate solution. The layers were separated, and the aqueous layer was extracted again with 2 × 1000 ml of ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated to an oil which was purified by silica gel chromatography (0-50% ethyl acetate in hexane). The product containing fractions were concentrated to obtain tert-butyl-3-gidroksitsiklogeptilkarbamata (21.1 g, 92 mmol, 67.3% yield). MS (ESI) m / z 230,3 [M + H]⁺. Two previous reaction was repeated starting with 9.52 g -cyclohept-2-enone and to obtain 9.27 g of tert-butyl-3-gidroksitsiklogeptilkarbamata. Two batches of tert-butyl-3-gidroksitsiklogeptilkarbamata then pooled. The combined material, 29.2 g, were separated into four component stereoisomers (two diastereomers and their corresponding enantiomers) by preparative chiral SFC, using multiple injections in three separate columns. First column: ChiralPak IC-H, 250 × 30 mm ID, isocratic 15% ethanol in CO₂, 38 ° C. Second column: ChiralCel OJ-H, 250 × 30 mm ID, isocratic 10% isopropanol in CO₂, 38 ° C. Third column: ChiralPak AD-H, 250 × 50 mm ID, isocratic 20% isopropanol in CO₂, 38 ° C. The separated isomers were characterized on column Phenomenex Lux Amylose-2, 250 × 4,6 mm ID, isocratic 15% ethanol in CO₂ (Run time 10 minutes) in an analytical scale and designated Intermediate 1 - Intermediate 4.

Intermediate 1: 5.4 g (23.55 mmol, 18.5% yield of SFC purification). Retention time: 4.065 minutes.

Intermediate 2: 5.5 g (23.98 mmol, 18.8% yield of SFC purification). Retention time: 3.019 minutes.

Intermediate 3: 7.2 g (31.34 mmol, 24.6% yield of SFC purification). Retention time: 3.675 minutes.

Intermediate 4: 4.7 g (20.50 mmol, 16.1% yield of SFC purification). Retention time: 3.263 minutes.

C. (1S, 3R) -3-Aminotsiklogeptanol, (1R, 3R) -3-aminotsiklogeptanol, (1S, 3S) -3-aminotsiklogeptanol, (1R, 3S) -3-aminotsiklogeptanol. 75 mg (0.327 mmol) of each substance, which corresponded to intermediate 1 - Intermediate 4 from step B, independently dissolved in DCM (11.25 mL) and TFA (3.75 mL). Each reaction mixture was allowed to stir overnight at ambient temperature. The solvent of each reaction mixture were removed in vacuo, and then each reaction mixture was dissolved in a mixture of 4N hydrochloric acid in dioxane (5 ml) and methanol (5 ml). Each reaction mixture was stirred overnight at ambient temperature. Each of the four reaction mixtures (each containing individual isomer aminotsiklogeptanola-3) was concentrated under reduced pressure and used without further purification. MS (ESI) m / z 130,2 [M + H]⁺ for each. Designation of Intermediate 1 - Intermediate 4 saved for tracking purposes.

D. 4 - ((1R, 3S) -3-Gidroksiciklogeptilamino) -2 - ((1R, 4R) -4-metoksiciklogeksilamino) pyrimidine-5-carboxamide, 4 - ((1R, 3R) -3-gidroksiciklogeptilamino) -2 - ((1 R, 4R) -4-metoksiciklogeksilamino) pyrimidine-5-carboxamide, 4 - ((1S, 3R) -3-gidroksiciklogeptilamino) -2 - ((1R, 4R) -4-metoksiciklogeksilamino) pyrimidine-5-carboxamide , 4 - ((1S, 3S) -3-gidroksiciklogeptilamino) -2 - ((1R, 4R) -4-metoksiciklogeksilamino) pyrimidine-5-carboxamide. To the concentrate každomu (Intermediate product 1 - Intermediate Product 4) are stadii dobavlâli S 2 - ((1R, 4R) -4-metoksiciklogeksilamino) -4- (methylsulfonyl) pyrimidine-5-carboxamide (53.7 mg, .1635 mmol) of , NMP (2 ml) and DIEA (0.286 ml, 1.635 mmol). The obtained mixture of 4 peremešivali at 80 ° C in a week overnight. Reakcionnye rastvory independently from each other in kondensirovali ponižennom pressure, and the products were purified by preparative reverse phase HPLC (5-80% acetonitrile + 0.1% trifluoroacetic acid in water + 0.1% trifluoroacetic acid, over 30 min). Fractions containing product were concentrated under reduced pressure. The resulting solids were independently dissolved in methanol (5 ml) was passed through a SPE tube with a Varian Stratospheres HCO3 polymer to remove TFA (0.9 mmol bicarbonate equiv.) And then concentrated under reduced pressure to give the compounds of the title, 1 as Peak - Peak 4. The single isomers (peak 1 - Peak 4), characterized in column 250 × 4,6 mm ChiralPak AD-H in an analytical scale, ID, isocratic 40% methanol + 0.1% diethylamine in CO The product containing eluate was concentrated under reduced pressure. The resulting solids were independently dissolved in methanol (5 ml) was passed through a SPE tube with a Varian Stratospheres HCO3 polymer to remove TFA (0.9 mmol bicarbonate equiv.) And then concentrated under reduced pressure to give the compounds of the title, 1 as Peak - Peak 4. The single isomers (peak 1 - Peak 4), characterized in column 250 × 4,6 mm ChiralPak AD-H in an analytical scale, ID, isocratic 40% methanol + 0.1% diethylamine in CO The product containing eluate was concentrated under reduced pressure. The resulting solids were independently dissolved in methanol (5 ml) was passed through a SPE tube with a Varian Stratospheres HCO3 polymer to remove TFA (0.9 mmol bicarbonate equiv.) And then concentrated under reduced pressure to give the compounds of the title, 1 as Peak - Peak 4. The single isomers (peak 1 - Peak 4), characterized in column 250 × 4,6 mm ChiralPak AD-H in an analytical scale, ID, isocratic 40% methanol + 0.1% diethylamine in CO₂ (10 minutes run time).

PIC 1: 10.3 mg (0.027 mmol); ¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 9.02 (d, J = 6,64 Hz, 1 H), 8.33 (s, 1H), 7.04 (d, J = 7,42 Hz, 1H), 4, 44 (br. s., 1H), 4.19 (br. s., 1H), 3,56-3,90 (m, 2 H), 3.23 (s, 3H), 3.09 (br . s., 1H), 1,04-2,11 (m, 18H). MS (ESI) m / z 378,3 [M + H]⁺. Retention time: 2.534 minutes.

Peak 2: 30.0 mg (0.079 mmol); ¹H-ЯМР (400 МГц, DMCO-d₆) Δ hr. / Million 8.95 (d, J = 6,25 Hz, 1 H), 8.33 (s, 1H), 7.06 (d, J = 7,03 Hz, 1H), 4, 46 (d, J = 3,12 Hz, 1H), 3,86-4,18 (m, 1H), 3,48-3,81 (m, 2H), 3.23 (s, 3H), 3 09 (br. s., 1H), 1,06-2,16 (m, 18H). MS (ESI) m / z 378,5 [M + H]⁺. Retention time: 3.848 minutes.

PIC 3: 22.0 mg (0.058 mmol); ¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 9.02 (d, J = 7,03 Hz, 1H), 8.33 (s, 1H), 7.04 (d, J = 7,03 Hz, 1H), 4.45 (d, J = 3,12 Hz, 1H), 4.20 (br. s., 1H), 3,56-3,91 (m, 2H), 3.23 (s, 3H), 3.09 (br. s., 1H), 1,06-2,12 (m, 18H). MS (ESI) m / z 378,5 [M + H]⁺. Retention time: 4.557 minutes.

PIC 4: 22.5 mg (0 060 mmol); ¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8.95 (d, J = 6,64 Hz, 1H), 8.33 (s, 1H), 6,47-7,21 (m, 1H), 4.46 (d, J = 3,12 Hz, 1H), 3.94 (br. s., 1H), 3.73 (br. s., 2H), 3.23 (s, 3H), 3.09 (br. c ., 1H), 1,04-2,18 (m, 18H). MS (ESI) m / z 378,3 [M + H]⁺. Retention time: 2.607 minutes.

Because the chemical shift of the proton at ~ 4.2 hr. / Million Peak 1 and Peak 3 compared to ~ 3.94 hr. / Mn in peaks 2 and 4, and also the proton shift at ~ 9.02 hr. / Million peak 1 and peak 3 compared to ~ 8.95 hr. / million Peaks 2 and 4, the data ¹H-NMR, shown above, were interpreted as follows: Peak 1 and peak 3 are enantiomers. Peak 2 and Peak 4 are enantiomers.

Alternatively, it was used chiral synthesis pathway, as described below.

Example 12V: 4 - ((1R, 3S) -3-gidroksiciklogeptilamino) -2 - ((1R, 4R) -4-metoksiciklogeksilamino) pyrimidine-5-carboxamide

<img file="00000113.jpg" he="37" wi="63" img-format="tif" img-content="undefined" />

A. cycloheptyl-2-enol. To a solution -cyclohept-2-enone (10 g, 91 mmol) and cerium (III) chloride heptahydrate (33.8 g, 91 mmol) in methanol (45.5 ml) was added portionwise sodium borohydride (3.43 g, 91 mmol ) during 10 min period with cooling in a water bath. The reaction mixture was then stirred for 2.5 hours at room temperature. The reaction mixture was quenched by addition of water (45 mL) and then extracted with pentane (4 × 100 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give compound the title compound (8.30 g, 74.0 mmol, 82% yield) as an oil which was used without further purification.¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 5,49-5,71 (m, 2H), 4.66 (d, J = 4,29 Hz, 1H), 4.05-4.20 (m, 1H), 1, 07-2,14 (m, 8H).

B. cycloheptyl-2-enyl methyl carbonate. To a solution of cycloheptyl-2-enol (8.3 g, 74.0 mmol) in DCM (227 mL) and pyridine (35.9 mL, 444 mmol) was added methyl chloroformate (14.24 mL, 185 mmol) under ice bath at a temperature level T &lt;10 ° C. After complete addition, the reaction mixture was allowed to stir and warm to ambient temperature overnight. The reaction mixture was washed with 2 × 150 ml of 1N aqueous hydrochloric acid. The combined washings were back-extracted with 100 ml of DCM. The combined DCM layers were then washed with 150 ml of saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give compound the title compound (11.95 g, 70.2 mmol, 95% yield) as an oil .¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 5.83 (dddd, J = 11.81, 7.03, 5.17, 2.15 Hz, 1H), 5.65 (d, J = 11,71 Hz, 1H), 5.17 (d, J = 6,64 Hz, 1H), 4.71 (d, J = 4,30 Hz, 1H), 3.69 (s, 2H), 1,99-2,23 (m , 2H), 1.79-1.94 (m, 2H), 1.56-1.72 (m, 3H), 1.34 (d, J = 3,51 Hz, 1H).

C. (R) -2- (cycloheptyl-2-enyl) isoindoline-1,3-dione. Potassium salt of phthalimide (19.59 g, 106 mmol), allylpalladium chloride dimer (0.477 g, 1.322 mmol), (1S, 2S) - (-) - 1,2-diaminocyclohexane-N, N'-bis (2'- difenilfosfinobenzoil) (2.74 g, 3.97 mmol), tetrahexylammonium bromide (50.6 g, 116 mmol) and DCM (212 mL) were combined in a round bottom flask. The flask was flushed with nitrogen and then placed in an ultrasonic bath for 10 minutes. Then the flask was added in one portion -cyclohept-2-enilmetilkarbonat (9.00 g, 52.9 mmol) and the resulting mixture was stirred under nitrogen at ambient temperature overnight. The reaction mixture was quenched by adding 50 ml of water and then extracted with 3 × 100 ml of diethyl ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated to an oil which slowly otvezhdalos overnight. The solids were triturated with methanol (50 ml) and filtered to give 7.6 g of crude product. The crude solid was recrystallized from methanol and dried in vacuo to afford compound the title compound (6.70 g, 27.8 mmol, 52.5% yield) as a solid, which, as determined by analytical chiral chromatography SFC (Phenomenex Lux Cellulose-4, 250 × 4,6 mm ID, 5-50% isopropanol in CO₂, 13 minute gradient) had a% e.e. 97,2 (S isomer was obtained analogously to standard using a ligand (1R, 2R) - (-) - 1,2-diaminocyclohexane-N, N'-bis (2'-difenilfosfinobenzoil).¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 7,41-8,22 (m, 4H), 5,62-5,97 (m, 2H), 4.77 (d, J = 11,32 Hz, 1H), 2, 01-2,29 (m, 3H), 1.87-2.00 (m, 1H), 1.62-1.78 (m, 2H), 1,45-1,61 (m, 1H), 1.17-1.32 (m, 1H). MS (ESI) m / z 242,3 [M + 1]⁺.

D. 2 - ((1R, 2S, 3S) -2-Bromo-3-gidroksitsiklogeptil) isoindoline-1,3-dione. To a solution of (R) -2- (cycloheptyl-2-enyl) isoindoline-1,3-dione (4.00 g, 16.58 mmol) in chloroform (40.0 mL) and ethanol (1.400 ml) was added N- bromosuccinimide (3.78 g, 21.22 mmol) as a solid over 5 minutes at room temperature. After the addition was complete, the reaction mixture was stirred at room temperature overnight under nitrogen. A further portion of N-bromosuccinimide (1.9 g) and 1.4 ml of ethanol, and the mixture was allowed to stir at room temperature overnight under nitrogen. To the mixture was added a third portion of N-bromosuccinimide (1.0 g) and an additional portion of 1.4 mL of ethanol, and then stirred at room temperature for a third night under a nitrogen atmosphere. The reaction mixture was then concentrated to dryness. The resulting solid was triturated with 25 mL of fresh chloroform. The solids were filtered, washed with chloroform and the filtrate concentrated to dryness under reduced pressure. Was added THF (40 ml) and 1N hydrochloric acid (aq.) (10 mL) to the concentrated filtrate and the resulting mixture was stirred at room temperature for 90 minutes. The solution was concentrated under reduced pressure to remove the THF. The concentrate was diluted with 125 ml ethyl acetate and 75 mL of 1: 1 water: saturated aqueous sodium bicarbonate solution. The layers were separated, and the aqueous layer was again extracted with 75 ml of ethyl acetate. The combined ethyl acetate layers were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give an oil, which was purified by silica gel chromatography (0-30% ethyl acetate in hexane). The fractions containing the desired product were concentrated under reduced pressure to a compound of the title (3.9 g, 11.53 mmol, 69.6% yield) as a solid.¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 7.88 (d, J = 7,42 Hz, 4H), 5.48 (d, J = 5,47 Hz, 1H), 4.73 (dd, J = 10,54, 6.25 Hz, 1H), 4,24-4,38 (m, 1H), 3.91-3.99 (m, 1H), 2.32 (br. s., 1H), 1,67- 1.96 (m, 5H), 1.40-1.60 (m, 2H). MS (ESI) m / z 320,1 [M-18]⁺. Experiment COSY and NMR data¹H-NMR, above, was used to verify regiochemistry bromohydrin. NOE (by NOESY experiments) were observed between the protons on the carbon-carbon amino and hydroxyl groups. This confirms the cis arrangement of two functional groups (trans location, which is devoid of the spatial proximity would not show such an effect).

E. 2 - ((1R, 3S) -3-Gidroksitsiklogeptil) isoindoline-1,3-dione. To a solution of 2 - ((1R, 2S, 3S) -2-bromo-3-gidroksitsiklogeptil) isoindoline-1,3-dione (4.2 g, 12.42 mmol) in toluene (69 ml) and methanol (6 9 ml) was added tributyltin hydride (4.34 mL, 16.14 mmol) via syringe over 10 minutes under a nitrogen atmosphere, and then - in one portion 2,2'-azobis (2-methylpropanenitrile) (0.204 g, 1.242 mmol) . The reaction mixture was then heated at reflux overnight under nitrogen. The reaction mixture was concentrated to dryness under reduced pressure to give a solid which was purified by silica gel chromatography (0-50% ethyl acetate in hexane). The fractions containing the desired product were concentrated under reduced pressure to obtain the compound of the title (2.6 g, 10.03 mmol, 81% yield) as a solid.¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 7,72-7,98 (m, 4H), 4.58 (d, J = 4,29 Hz, 1H), 4.14 (br. S., 1H), 3.67 (dt, J = 6.25, 3.90 Hz, 1H), 2.24-2.40 (m, 1H), 2,04-2,19 (m, 1H), 1.81-1.95 (m, 2H), 1,39-1,80 (m, 6H). MS (ESI) m / z 259,9 [M + H]⁺.

E. (1S, 3R) -3-Aminotsiklogeptanol. 2 - ((1R, 3S) -3-gidroksitsiklogeptil) isoindoline-1,3-dione (1800 mg, 6.94 mmol) was dissolved in methanol (86.80 ml). To the solution was added hydrazine monohydrate (0.354 ml, 7.29 mmol) and the resulting mixture was stirred overnight at reflux. A further portion of 0.2 equivalents. (0.067 mL) of hydrazine and the mixture was refluxed for two nights. The reaction mixture was concentrated to a volume of a few milliliters and filtered. The solids were washed with 50 ml of DCM and chloroform each and the filtrate was concentrated under reduced pressure to give compound the title compound (174 mg, 1.347 mmol, 19.40% yield) as an oil which was used without further purification. MS (ESI) m / z 130,2 [M + H]⁺.

F. 4 - ((1R, 3S) -3-Gidroksitsiklogeptilamino) -2 - ((1R, 4R) -4-metoksitsiklogeksilamino) pyrimidine-5-carboxamide. To a solution of 2 - ((1R, 4R) -4-metoksitsiklogeksilamino) -4- (methylsulfinyl) pyrimidine-5-carboxamide (105 mg, 0.336 mmol) in NMP (1 ml) was added (1S, 3R) -3-aminotsiklogeptanol ( 87 mg, 0.672 mmol) and DIEA (0.235 mL, 1.344 mmol). The resulting mixture was heated to 80 ° C for 4 hours and then allowed to cool to ambient temperature overnight. The reaction mixture was concentrated under reduced pressure and the solid residue was purified by preparative reverse phase HPLC (5-80% acetonitrile + 0.1% TFA in water + 0.1% TFA, over 30 min). Fractions containing product were concentrated under reduced pressure. The resulting solid was again dissolved in methanol (5 ml), was passed through a SPE tube with a Varian Stratospheres HCO3 polymer to remove TFA (0.9 mmol bicarbonate equiv ..), and then concentrated under reduced pressure. The solid residue was triturated with acetonitrile and concentrated under reduced pressure to give compound the title compound (67 mg, 0.177 mmol, 52.8% yield) as a solid.¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8.96 (d, J = 5,86 Hz, 1H), 8.33 (s, 1H), 7.00-7.16 (m, 1H), 4.46 (d, J = 3,90 Hz, 1H), 3,85-4,09 (m, 1H), 3,56-3,81 (m, 2H), 3.23 (s, 3H), 2,97-3 15 (m, 1H), 1,71-2,14 (m, 7H), 1.51 (d, J = 10,15 Hz, 11H). MS (ESI) m / z 378,3 [M + H]⁺.

Analytical chiral SFC, using a column ChiralPak AD-H (250 × 4,6 mm ID, isocratic 40% methanol + 0.1% diethylamine in CO₂, Run time 10 minutes) was used to set the relationship between the single isomer obtained in the synthesis of chiral and isomer obtained previous embodiment receipt of all four stereoisomers. It has been found that a substance obtained by this by chiral synthesis, has the same retention time (3,848 minutes) Peak 2 like in Example 12A, thus:

AUC = 2 4 - ((1R, 3S) -3-gidroksiciklogeptilamino) -2 - ((1R, 4R) -4-metoksiciklogeksilamino) pyrimidine-5-carboxamide.

Based on the data ¹H-NMR, it was found that Peak 2 and Peak 4 are the enantiomeric pair of Example 12A, thus:

AUC = 4 4 - ((1S, 3R) -3-gidroksiciklogeptilamino) -2 - ((1R, 4R) -4-metoksiciklogeksilamino) pyrimidine-5-carboxamide.

Furthermore, it follows that the intermediate product 2 which was used to prepare Peak 2 in Example 12A, may then be defined as tert-butyl (1R, 3S) -3-gidroksitsiklogeptilkarbamat and intermediate 4 which was used to prepare Peak 4 in example 12A, may then be defined as tert-butyl (1S, 3R) -3-gidroksitsiklogeptilkarbamat.

For identifying the absolute stereochemistry of the intermediate 1 and intermediate 3 (and thus, the absolute stereochemistry of Peak 1 and Peak 3) in Example 12A, the following experiment was performed.

Mitsunobu reaction of tert-butyl (1R, 3R) -3-gidroksitsiklogeptilkarbamata to obtain tert-butyl- (1R, 3S) -3-gidroksitsiklogeptilkarbamata.

<img file="00000114.jpg" he="35" wi="31" img-format="tif" img-content="undefined" />

A. tert-Butyl (1R, 3S) -3-gidroksitsiklogeptilkarbamat. Intermediate 3 Step B of Example 12A was dissolved in THF (31, 700 ml). The mixture was cooled to 0 ° C in an ice bath under nitrogen atmosphere was added in one portion initially chloroacetic acid (261 mg, 2.76 mmol) followed by triphenylphosphine (723 mg, 2.76 mmol). Was added dropwise a solution of diethylazodicarboxylate (0.437 mL, 2.76 mmol) before addition of the next drop waiting disappearance of yellow color. After completion of the addition, the solution was stirred at 0 ° C under a nitrogen atmosphere for 3 hours. The reaction mixture was concentrated under reduced pressure and the resulting oil was purified by silica gel chromatography (0-40% ethyl acetate in hexane). The pure product-containing fractions were combined and concentrated under reduced pressure, and then again dissolved in methanol (16 mL). To the solution was added sodium carbonate (186 mg, 1.755 mmol) and the resulting mixture was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to dryness. The solid residue was diluted with 50 mL of 1: 1 water: saturated aqueous sodium bicarbonate solution and 75 ml of DCM. The layers were separated, and the aqueous layer was again extracted with 50 ml DCM. The combined DCM layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give material which was identical to the retention time in analytical SFC, as an intermediate product of step 2 in Example 12A, or tert-butyl (1R, 3S) -3-gidroksitsiklogeptilkarbamat (417 mg, 1.818 mmol, 72.5% yield) as a solid. The reaction mixture was concentrated under reduced pressure to dryness. The solid residue was diluted with 50 mL of 1: 1 water: saturated aqueous sodium bicarbonate solution and 75 ml of DCM. The layers were separated, and the aqueous layer was again extracted with 50 ml DCM. The combined DCM layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give material which was identical to the retention time in analytical SFC, as an intermediate product of step 2 in Example 12A, or tert-butyl (1R, 3S) -3-gidroksitsiklogeptilkarbamat (417 mg, 1.818 mmol, 72.5% yield) as a solid. The reaction mixture was concentrated under reduced pressure to dryness. The solid residue was diluted with 50 mL of 1: 1 water: saturated aqueous sodium bicarbonate solution and 75 ml of DCM. The layers were separated, and the aqueous layer was again extracted with 50 ml DCM. The combined DCM layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give material which was identical to the retention time in analytical SFC, as an intermediate product of step 2 in Example 12A, or tert-butyl (1R, 3S) -3-gidroksitsiklogeptilkarbamat (417 mg, 1.818 mmol, 72.5% yield) as a solid.¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 6,63-6,87 (m, 1H), 4.44 (d, J = 3,90 Hz, 1H), 3,47-3,71 (m, 1H), 0 99-1,98 (m, 19H). MS (ESI) m / z 260,1 [M + 1]⁺.

Intermediate 3 Step B of Example 12A was thus identified as tert-butyl (1R, 3R) -3-gidroksitsiklogeptilkarbamat. Peak 3 step D, the intermediate derived from Example 12A 3 thus was designated as 4 - ((1R, 3R) -3-gidroksitsiklogeptilamino) -2 - ((1R, 4R) -4-metoksitsiklogeksilamino) pyrimidin-5- carboxamide.

Since Peak 1 and peak 3 are enantiomers according ¹H-NMR as described in Example 12A, Peak 1 can be designated as 4 - ((1S, 3S) -3-gidroksitsiklogeptilamino) -2 - ((1R, 4S) -4-metoksitsiklogeksilamino) pyrimidine-5-carboxamide. Thus, the intermediate product of step 1 in Example 12A, which was used for the Peak 1 in step D of Example 12A, can be referred to as tert-butyl (1S, 3S) -3-gidroksitsiklogeptilkarbamat.

Example 13 4 - ((1R, 3S) -3-Gidroksiciklogeksilamino) -2 - ((1R, 4R) -4- (2,2,2-triftorétoksi) ciklogeksilamino) pyrimidine-5-carboxamide, 4 - ((1 R , 3S) -3-gidroksiciklogeksilamino) -2 - ((1S, 4S) -4- (2,2,2-triftorétoksi) ciklogeksilamino) pyrimidine-5-carboxamide

<img file="00000115.jpg" he="38" wi="144" img-format="tif" img-content="undefined" />

A. 4 - ((1R, 3S) -3-hydroxycyclohexylamino) -2 - ((1R, 4R) -4- (2,2,2-trifluoroethoxy) cyclohexylamino) pyrimidine-5-carboxamide and 4 - ((1R, 3S) -3-hydroxycyclohexylamino) -2 - ((1S, 4S) -4- (2,2,2-trifluoroethoxy) cyclohexylamino) pyrimidine-5-carboxamide. To a stirred solution of 4 - ((1R, 3S) -3-hydroxycyclohexylamino) -2- (methylsulfonyl) pyrimidine-5-carboxamide (440 mg, 1.400 mmol; synthesis described herein) and trihydrochloride bis-4- (2,2 , 2-trifluoroethoxy) cyclohexanamine (529 mg, 2.099 mmol) in DMSO (6.964 mL) was added DIEA (0.978 mL, 5.60 mmol). The resulting mixture was allowed to stir overnight at 100 ° C. The crude reaction mixture was concentrated and purified by silica gel chromatography (0-10% methanol / dichloromethane) and then purified by reversed phase silica gel column chromatography (methanol / water with the modifier of 0.1% formic acid). Fractions containing product were neutralized and concentrated to give 4 - ((1R, 3S) -3-hydroxycyclohexylamino) -2- (4- (2,2,2-trifluoroethoxy) cyclohexylamino) pyrimidine-5-carboxamide (135 mg, 0.313 mmol, 22.36% yield) as a mixture of 2 stereoisomers. MS (ESI) m / z 432,2 [M + H]⁺. This mixture was separated using chiral liquid chromatography at ultrahigh temperatures (Column AD-H), to yield 87.8 mg (0.203 mmol) of the unit, faster eluting stereoisomer (PIC 1) and 24.2 mg (0.056 mmol) of the second unit, slowly stereoisomer eluted (Peak 2).

Then repeat the same sequence of reactions by using (1R, 4R) -4- (2,2,2-trifluoroethoxy) cyclohexanamine, which was prepared as follows.

(1R, 4R) -4- (benzylamino) cyclohexanol. A mixture of (1R, 4R) -4-aminocyclohexanol (230 g, 2 mol), benzaldehyde (212 g, 2 mol) and<img file="00000116.jpg" he="5" wi="6" img-format="tif" img-content="undefined" /> molecular sieves in methanol (2 L) was refluxed under a nitrogen atmosphere for 3 hours. The mixture was cooled using ice-water bath, and carefully dobavyali small portions sodium borohydride (72 g, 2 mol). After complete addition, the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the solid residue was partitioned between dichloromethane (2 L) and water (1 L). The dichloromethane layer was separated, washed with saturated aqueous sodium chloride, and was used directly in the next step.

Benzyl benzyl ((1R, 4R) -4-hydroxycyclohexyl) carbamate. To a solution of (1R, 4R) -4- (benzylamino) cyclohexanol obtained in the preceding step, in dichloromethane was added a saturated aqueous solution of sodium bicarbonate (1.5 L), and this two-phase system was slowly added benzyl chloroformate (358.2 g, 2 , 1 mol) at 0 ° C. After complete addition, the reaction mixture was stirred at room temperature for another hour, then the organic phase was separated and evaporated. After concentration, the solid residue was purified by silica gel chromatography (0-30% ethyl acetate in hexane) to give the compound of the title as a colorless liquid (400 g, 1.18 mol, 59% yield for two steps). Both steps were repeated to give a total amount of 800 g of benzyl benzyl ((1R, 4R) -4-hydroxycyclohexyl) carbamate.

Benzyl benzyl ((1R, 4R) -4- (2,2,2-trifluoroethoxy) cyclohexyl) carbamate. To a solution of benzyl benzyl ((1R, 4R) -4-hydroxycyclohexyl) carbamate (400 g, 1.18 mol) in chloroform (2 L) was added 50% aqueous solution of fluoroboric acid (20 ml) and the jet diazotriftoretana (svezhepoluchen by mixing triftoretanamina hydrochloride (1.6 kg, 11.8 mol) and NaNO₂ (814 g, 11.8 mol) in water (3 L) and then the reaction solution barbatirovaniya above). The reaction was monitored by TLC and after completion of the addition of a saturated aqueous potassium carbonate solution (300 mL). The chloroform layer was separated, concentrated under reduced pressure and purified by column chromatography (0-10% ethyl acetate in hexane) to yield benzyl benzyl ((1R, 4R) -4- (2,2,2-trifluoroethoxy) cyclohexyl) carbamate (192 g, 0.456 mol, 38% yield). This reaction was repeated to give another batch of benzyl benzyl ((1R, 4R) -4- (2,2,2-trifluoroethoxy) cyclohexyl) carbamate (185 g, 0.439 mol).

(1R, 4R) -4- (2,2,2-trifluoroethoxy) cyclohexanamine. To a solution of benzyl benzyl ((1R, 4R) -4- (2,2,2-trifluoroethoxy) cyclohexyl) carbamate (377 g, 0.89 mol) in ethyl acetate (2 L) was added 20% palladium hydroxide on carbon (50 g ), and the mixture was stirred under a hydrogen atmosphere at a pressure of 55 psig. inch for 24 hours at room temperature. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting solid was dissolved in 2N hydrochloric acid (1.5 L) and the solution was washed with methyl tert-butyl ether (300 mL × 5). Was added solid potassium carbonate to adjust the pH greater than 10. The product was extracted into dichloromethane (500 ml × 5). The combined organic phases were dried and concentrated under reduced pressure.¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 4.01 (q, J = 8,8 Hz, 2H), 3,40-3,33 (m, 1H), 2,56-2,53 (m, 1H), 1, 94-1,92 (m, 2H), 1,75-1,72 (m, 2H), 1,24-1,15 (m, 2H), 1,08-0,97 (m, 2H); MS (ESI) m / z 198,2 [M + 1]⁺.

Using the above intermediate product it was shown that the substance obtained as the peak 1 corresponds to 4 - ((1R, 3S) -3-hydroxycyclohexylamino) -2 - ((1R, 4R) -4- (2,2,2-trifluoroethoxy) cyclohexylamino) pyrimidine-5-carboxamide, whereas the substance obtained as the peak 2, corresponding to 4 - ((1R, 3S) -3-hydroxycyclohexylamino) -2 - ((1S, 4S) -4- (2,2,2- trifluoroethoxy) cyclohexylamino) pyrimidine-5-carboxamide.

Peak 1: 4 - ((1R, 3S) -3-gidroksiciklogeksilamino) -2 - ((1R, 4R) -4- (2,2,2-triftorétoksi) ciklogeksilamino) pyrimidine-5-carboxamide. ¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8.90 (d, J = 6,25 Hz, 1H), 8.34 (s, 1H), 7.46-7.52 (m, 1H), 7,07-7, 17 (m, 1H), 6.91 (dd, J = 8.59, 2.73 Hz, 1H), 4.60-4.76 (m, 1H), 4.02 (q, J = 9, 63 Hz, 2H), 3,39-3,96 (m, 4H), 0,92-2,24 (m, 16H). ¹⁹F ЯМР (376 МГц, ДМСО-d₆) δ ч./млн -76,47-72,01 (м, 3F). МС (ESI) m/z 432,0 [М+Н]⁺.

Peak 2: 4 - ((1R, 3S) -3-gidroksiciklogeksilamino) -2 - ((1S, 4S) -4- (2,2,2-triftorétoksi) ciklogeksilamino) pyrimidine-5-carboxamide. ¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8.90 (d, J = 6,64 Hz, 1H), 8.34 (br. S., 1H), 6,79-7,50 (m, 2H), 4.64 (br. s., 1H), 4.00-4.12 (m, 2H), 3.42 (d, J = 4,69 Hz, 4H), 0,91-2,25 (m, 16H) . ¹⁹F ЯМР (376 МГц, ДМСО-d₆) Δ hr. / Million -73.63 (t, J = 9,47 Hz, 3F). MS (ESI) m / z 432,0 [M + H]⁺.

Example 14: 2 - ((1R, 4R) -4- (Diftormetoksi) ciklogeksilamino) -4 - ((1R, 3S) -3-gidroksiciklogeksilamino) pyrimidine-5-carboxamide

<img file="00000117.jpg" he="38" wi="60" img-format="tif" img-content="undefined" />

A. Methyl 2-chloro-4 - ((1R, 3S) -3-hydroxycyclohexylamino) pyrimidine-5-carboxylate. To a stirred solution of methyl 2,4-dichloropyrimidine-5-carboxylate (4.00 g, 19.32 mmol) in THF (85 mL) was added DIEA (3.37 mL, 19.32 mmol). The resulting mixture was cooled to -78 ° C in a dry ice / acetone bath. A solution of (1S, 3R) -3-aminocyclohexanol (2.448 g, 21.25 mmol; prepared as described in Tetrahedron: Asymmetry 15: 2051-2056 (2004)) in 40 ml THF at such a level that the temperature remains -78 ° FROM. The resulting mixture was stirred at -78 ° C for 1 hour The reaction mixture was then concentrated to dryness and diluted with 200 ml of ethyl acetate and 75 mL of 1: 1. Water and saturated aqueous sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted with 100 ml of ethyl acetate again. The combined ethyl acetate layers were washed with 50 ml of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil which solidified on standing. The solid was triturated in diethyl ether (5 ml), filtered, washed with diethyl ether (5 ml) and dried in vacuo to give methyl 2-chloro-4 - ((1R, 3S) -3-hydroxycyclohexylamino) pyrimidine-5 carboxylate (3.7 g, 12.95 mmol, 67% yield) which was used without further purification. MS (ESI) m / z 286,0 [M + 1]⁺.

B. (1R, 4R) -4- (dibenzylamino) cyclohexanol. Trans-4-aminocyclohexanol was suspended in acetonitrile (500 ml) (25 g, 217 mmol). To the suspension was added benzyl bromide (54.2 mL, 456 mmol) and potassium carbonate (120 g, 868 mmol) and the resulting mixture was vigorously stirred overnight at room temperature. The reaction mixture was filtered through a Celite plug, and the plug washed thoroughly with acetonitrile. The filtrate was concentrated to give a white solid. The crude solid was purified by silica gel chromatography (0-60% ethyl acetate in hexane). The purified product-containing fractions were combined and concentrated to give (1R, 4R) -4- (dibenzylamino) cyclohexanol (25 g, 85 mmol, 39.0% yield) as a white solid.¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 7.26-7.36 (m, 8H), 7.16-7.22 (m, 2H), 4.43 (d, J = 4,69 Hz, 1H), 3, 55 (s, 4H), 3.27-3.33 (m, 1H), 2.28-2.40 (m, 1H), 1,69-1,88 (m, 4H), 1.40 ( qd, J = 12.56, 2.93 Hz, 2H), 0,89-1,05 (m, 2H); MS (ESI) m / z 296,3 [M + 1]⁺.

C. (1R, 4R) -N, N-dibenzyl-4- (difluoromethoxy) cyclohexanamine. (1R, 4R) -4- (dibenzylamino) cyclohexanol (5 g, 16.93 mmol) and copper iodide (I) (0,645 g, 3.39 mmol) was dissolved in 170 ml of acetonitrile and heated to 45 ° C in a nitrogen atmosphere . To this mixture was added a solution of 2,2-difluoro-2- (fluorosulfonyl) acetic acid (3.50 mL, 33.9 mmol) in 30 ml of acetonitrile for 10 minutes. After completion of the addition the mixture was stirred at 45 ° C under a nitrogen atmosphere for 1 h. Then, after 10 minutes an additional portion of reagent 2,2-difluoro-2- (fluorosulfonyl) acetic acid (2.86 mL, 27.7 mmol) in 30 ml of acetonitrile. The reaction mixture was stirred for an additional 1 hour at 45 ° C under a nitrogen atmosphere. The volatiles were then removed by evaporation and the solid residue was diluted with 175 ml ethyl acetate and 75 mL of 1: 1, water and a saturated aqueous solution of sodium bicarbonate. The resulting biphasic mixture containing solids was filtered through a sintered glass Buchner funnel. The layers of the filtrate were separated, and the aqueous layer was extracted with 50 ml of ethyl acetate. The combined ethyl acetate layers were washed with 50 mL of 1: 1 mixture of saturated sodium chloride solution and water, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. The crude oil was purified by silica gel chromatography (0-30% ethyl acetate in hexane). Fractions containing product were combined and concentrated to give (1R, 4R) -N, N-dibenzyl-4- (difluoromethoxy) cyclohexanamine (3.12 g, 9.03 mmol, 53.4% ​​yield) as an oil which was It solidified to an off-white solid. filtered through a sintered glass Buchner funnel. The layers of the filtrate were separated, and the aqueous layer was extracted with 50 ml of ethyl acetate. The combined ethyl acetate layers were washed with 50 mL of 1: 1 mixture of saturated sodium chloride solution and water, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. The crude oil was purified by silica gel chromatography (0-30% ethyl acetate in hexane). Fractions containing product were combined and concentrated to give (1R, 4R) -N, N-dibenzyl-4- (difluoromethoxy) cyclohexanamine (3.12 g, 9.03 mmol, 53.4% ​​yield) as an oil which was It solidified to an off-white solid. filtered through a sintered glass Buchner funnel. The layers of the filtrate were separated, and the aqueous layer was extracted with 50 ml of ethyl acetate. The combined ethyl acetate layers were washed with 50 mL of 1: 1 mixture of saturated sodium chloride solution and water, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. The crude oil was purified by silica gel chromatography (0-30% ethyl acetate in hexane). Fractions containing product were combined and concentrated to give (1R, 4R) -N, N-dibenzyl-4- (difluoromethoxy) cyclohexanamine (3.12 g, 9.03 mmol, 53.4% ​​yield) as an oil which was It solidified to an off-white solid. filtered and concentrated to an oil. The crude oil was purified by silica gel chromatography (0-30% ethyl acetate in hexane). Fractions containing product were combined and concentrated to give (1R, 4R) -N, N-dibenzyl-4- (difluoromethoxy) cyclohexanamine (3.12 g, 9.03 mmol, 53.4% ​​yield) as an oil which was It solidified to an off-white solid. filtered and concentrated to an oil. The crude oil was purified by silica gel chromatography (0-30% ethyl acetate in hexane). Fractions containing product were combined and concentrated to give (1R, 4R) -N, N-dibenzyl-4- (difluoromethoxy) cyclohexanamine (3.12 g, 9.03 mmol, 53.4% ​​yield) as an oil which was It solidified to an off-white solid.¹Н-ЯМР (400 МГц, DMCO-d₆) Δ hr. / Million 7.26-7.38 (m, 8H), 7.17-7.23 (m, 2H), 6.66 (s, 1H), 3.97 (t, J = 4 , 49 Hz, 1H), 3.57 (s, 4H), 2.36-2.47 (m, 1H), 1.98 (d, J = 10,54 Hz, 2H), 1.83 (d , J = 12,10 Hz, 2H), 1.49 (d, J = 12,89 Hz, 2H), 1.22 (d, J = 12,49 Hz, 2H). ¹⁹F ЯМР (376 МГц, ДМСО-d₆) d ч./млн -79,28 (д, J=73,00 Гц, 2F). MC(ESI) m/z 346,1 [M+1]⁺.

D. (1R, 4R) -4- (difluoromethoxy) cyclohexanamine. (1R, 4R) -N, N-Dibenzyl-4- (difluoromethoxy) cyclohexanamine (1.6 g, 4.63 mmol) was dissolved in ethanol (23 mL) in a Parr shake flask and added 20 wt% palladium hydroxide on carbon ( 0.650 g, 0.926 mmol). The container is discharged and placed on a Parr shaker apparatus and shaken under a hydrogen atmosphere at 50 psi. inch overnight. Palladium hydroxide was removed by filtration through pre-wetted (ethanol) a pad of celite. The filter cake is thoroughly washed with ethanol. The filtrate was concentrated to an oil which was dissolved in 100 ml of ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil which solidified to afford (1R, 4R) -4- (difluoromethoxy) cyclohexanamine (0.621 g, 3.76 mmol, 81% yield).¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 6,46-6,93 (m, 1H), 3.96 (s, 1H), 2.52-2.59 (m, 1H), 1.84-1.95 (m , 2H), 1.68-1.79 (m, 2H), 1.29-1.43 (m, 2H), 1,01-1,14 (m, 2H). ¹⁹F ЯМР (376 МГц, ДМСО-d₆) δ ч./млн -78,93 (д, J=91,00 Гц, 2F). МС (ESI) m/z 166,2 [М+1]⁺.

E. Methyl 2 - ((1R, 4R) -4- (difluoromethoxy) cyclohexylamino) -4 - ((1R, 3S) -3 hydroxycyclohexylamino) pyrimidine-5-carboxylate. To a stirred mixture of methyl 2-chloro-4 - ((1R, 3S) -3-hydroxycyclohexylamino) pyrimidine-5-carboxylate (300 mg, 1.050 mmol) and (1R, 4R) -4- (difluoromethoxy) cyclohexanamine (260 mg , 1.575 mmol) in DMSO (5 mL) was added DIEA (0.550 mL, 3.15 mmol). The resulting mixture was stirred at 70 ° C for 1 h. The crude reaction mixture was concentrated and then purified by silica gel chromatography (0-60% ethyl acetate in hexane). Fractions containing product were combined and concentrated to give methyl 2 - ((1R, 4R) -4- (difluoromethoxy) cyclohexylamino) -4 - ((1R, 3S) -3-hydroxycyclohexylamino) pyrimidine-5-carboxylate (165mg , 0.398 mmol, 37.9% yield).¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8,37-8,49 (m, 1H), 8.06 (d, J = 7,42 Hz, 1H), 7,22-7,55 (m, 1H), 6, 49-6,94 (m, 1H), 4,67-4,76 (m, 1H), 3,75-4,10 (m, 2H), 3.72 (s, 3H), 3,43- 3.69 (m, 2H), 1,63-2,24 (m, 8H), 1,08-1,54 (m, 8H). MC (ESI) m / z 415,5 [M + 1]⁺.

F. 2 - ((1R, 4R) -4- (difluoromethoxy) cyclohexylamino) -4 - ((1R, 3S) -3 hydroxycyclohexylamino) pyrimidine-5-carboxylic acid. To a stirred solution of methyl 2 - ((1R, 4R) -4- (difluoromethoxy) cyclohexylamino) -4 - ((1R, 3S) -3-hydroxycyclohexylamino) pyrimidine-5-carboxylate (170 mg, 0.410 mmol) in methanol ( 10 mL) in one portion was added an aqueous solution of sodium hydroxide (1 M, 3.075 mL, 3.075 mmol). The resulting mixture was allowed to stir at 50 ° C for 2 days. The reaction mixture was concentrated to remove methanol, diluted with an additional portion of water (10 ml) and slowly added an aqueous citric acid solution (2 M, 4.10 mL, 8.20 mmol). The resulting precipitate was stirred at room temperature for 30 minutes, filtered, and the solids were then thoroughly washed with water. The solids were dried in vacuo to give 2 - ((1R, 4R) -4- (difluoromethoxy) cyclohexylamino) -4 - ((1R, 3S) -3-hydroxycyclohexylamino) pyrimidine-5-carboxylic acid (117 mg, 0.292 mmol, 71.2% yield) as a solid, which was used without further purification. MS (ESI) m / z 401,5 [M + 1]⁺.

G. 2 - ((1R, 4R) -4- (difluoromethoxy) cyclohexylamino) -4 - ((1R, 3S) -3-hydroxycyclohexylamino) pyrimidine-5-carboxamide. To a stirred suspension of 2 - ((1R, 4R) -4- (difluoromethoxy) cyclohexylamino) -4 - ((1R, 3S) -3-hydroxycyclohexylamino) pyrimidine-5-carboxylic acid (117 mg, 0.292 mmol) and HATU (167 mg, 0.438 mmol) in DMF (2 mL) was added ammonium chloride (78 mg, 1.461 mmol) and DIEA (0.255 mL, 1.461 mmol). The resulting mixture was stirred at room temperature overnight. The crude reaction mixture was concentrated to remove volatiles and then purified by silica gel chromatography (10-90% ethyl acetate (containing 10% methanol saturated with ammonia) in hexane). The product fractions were combined and concentrated to give 2 - ((1R, 4R) -4- (difluoromethoxy) cyclohexylamino) -4 - ((1R, 3S) -3-hydroxycyclohexylamino) pyrimidine-5-carboxamide (35.3 mg, 0,¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8.90 (d, J = 6,64 Hz, 1H), 8.34 (br. S., 1H), 6,50-7,14 (m, 2H), 4.64 (br. s., 1H), 3,42-4,11 (m, 4H), 0,87-2,23 (m, 16H). ¹⁹F-ЯМР (376 МГц, ДМСО-d₆) δ ч./млн -78,98 (д, J=110,82 Гц, 2F). МС (ESI) m/z 400,5 [М+1]⁺.

Example 5: 4 - ((1R, 3S) -3-Metoksiciklogeksilamino) -2 - ((1R, 4R) -4-metoksiciklogeksilamino) pyrimidine-5-carboxamide

<img file="00000118.jpg" he="39" wi="58" img-format="tif" img-content="undefined" />

A. tert-Butyl (1R, 3S) -3-gidroksitsiklogeksilkarbamat. To a stirred solution of (1S, 3R) -3-aminocyclohexanol (1.0 g, 8.68 mmol; prepared as described in Tetrahedron: Asymmetry 15: 2051-2056 (2004)) in dioxane (8.04 mL) was added di- tert-butyl dicarbonate (2.369 g, 10.85 mmol). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated, sodium chloride (0.507 g, 8.68 mmol) and the resulting solution was diluted with water (20 ml) and hexane (20 mL). The suspension was stirred vigorously for 20 minutes, then filtered and the solids washed with hexane and dried in vacuo to give tert-butyl (1R, 3S) -3-gidroksitsiklogeksilkarbamata (1.7836 g, 8.28 mmol, 95% yield) as an off-white solid.¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 6.74 (d, J = 8,20 Hz, 1H), 4.58 (d, J = 4,29 Hz, 1H), 3.35-3.43 (m, 1H) , 3,11-3,27 (m, 1H), 1.90 (d, J = 11.32 Hz, 1H), 1.68-1.78 (m, 1H), 1.63 (d, J = 3.12 Hz, 2H), 1.37 (s, 9H), 0,87-1,23 (m, 4H); MS (ESI) m / z 216,3 [M + 1]⁺.

B. tert-Butyl (1R, 3S) -3-metoksitsiklogeksilkarbamat. To a solution of tert-butyl (1R, 3S) -3-gidroksitsiklogeksilkarbamata (1.78 g, 8.27 mmol) in anhydrous THF (8 ml) was added portionwise sodium hydride (0.230 g, 9.09 mmol) under nitrogen at 0 ° C. The mixture was warmed to room temperature and stirred for 30 min. A solution of iodomethane (0.824 mL, 13.23 mmol) in anhydrous THF (4 mL) was added dropwise to the mixture at 0 ° C, and the resulting mixture was stirred at room temperature for 20 h. The crude mixture was quenched with water (50 ml) and extracted ethyl acetate (3 × 50 mL). The combined organic layers were washed with saturated brine, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and then purified by silica gel chromatography (0-50% ethyl acetate in hexane). The product fractions were combined and concentrated to give tert-butyl (1R, 3S) -3-metoksitsiklogeksilkarbamata (1.0686 g, 4.66 mmol, 56.4% yield) as a white solid; MS (ESI) m / z 230,5 [M + 1]⁺.

C. (1R, 3S) -3-Metoksitsiklogeksanamin trifluoroacetate. To a solution of tert-butyl (1R, 3S) -3-metoksitsiklogeksilkarbamata (1.0686 g, 4.66 mmol) in anhydrous DCM (18.64 mL) was added TFA (3.59 mL, 46.6 mmol) and the resulting solution was stirred at room temperature for 1 hour. After the solvents were removed in vacuo and the resulting solid was triturated with ethyl ether (2 × 50 mL) to give trifluoroacetate (1R, 3S) -3-metoksitsiklogeksanamina (1,133 g , 4.66 mmol, 100% yield) as a white solid. The crude product was used without further purification in the next step.

D. Ethyl-4 - ((1R, 3S) -3-metoksitsiklogeksilamino) -2- (methylthio) pyrimidine-5-carboxylate. To a stirred solution of ethyl 4-chloro-2- (methylthio) pyrimidine-5-carboxylate (1.084 g, 4.66 mmol) and trifluoroacetate of (1R, 3S) -3-metoksitsiklogeksanamina (1.133 g, 4.66 mmol) in ethanol (18.63 mL) was added DIEA (2.434 mL, 13.97 mmol). The reaction mixture was heated to 60 ° C for 17 hours. The reaction mixture was cooled, cooled at room temperature and concentrated. The crude material was purified by silica gel chromatography (0-25% ethyl acetate in hexane) to give ethyl 4 - ((1R, 3S) -3-metoksitsiklogeksilamino) -2- (methylthio) pyrimidine-5-carboxylate (1.4284 g, 4.39 mmol, 94% yield) as a clear oil. MS (ESI) m / z 326,2 [M + 1]⁺.

E. 4 - ((1R, 3S) -3-Metoksitsiklogeksilamino) -2- (methylthio) pyrimidine-5-carboxylic acid. To a stirred solution of ethyl 4 - ((1R, 3S) -3-metoksitsiklogeksilamino) -2- (methylthio) pyrimidine-5-carboxylate (1.4284 g, 4.39 mmol) in ethanol (12.54 mL) was added aqueous sodium hydroxide solution (1N, 8.78 mL, 8.78 mmol) and the mixture was stirred for 2 hours. The reaction mixture was concentrated, diluted with water (50 ml) and then neutralized with stirring with an aqueous citric acid solution (2 M, 5.49 ml, 10.97 mmol). The residue was filtered, then washed with water (2 × 50 mL) and dried to give 4 - ((1R, 3S) -3-metoksitsiklogeksilamino) -2- (methylthio) pyrimidine-5-carboxylic acid (1.1679 g, 3.93 mmol, 89% yield) as a white solid.¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 13.22 (s, 1H), 8.65 (d, J = 7,03 Hz, 1H), 8.51 (s, 1H), 4.07-4.24 (m, 1H), 3.29-3.33 (m, 1H), 3.26 (s, 3H), 2.46 (s, 3H), 2.15 (d, J = 12,10 Hz, 1H), 1,63-1,88 (m, 3H), 1,21-1,48 (m, 4H); MS (ESI) m / z 298,1 [M + 1]⁺.

F. 4 - ((1R, 3S) -3-Metoksiciklogeksilamino) -2- (methylthio) pyrimidine-5-carboxamide. 4 - ((1R, 3S) -3-Metoksiciklogeksilamino) -2- (methylthio) pyrimidine-5-karbonovuû acid (1.1662 g, 3.92 mmol) and HATU (2.237 g, 5.88 mmol) in DMF peremešivali (7.84 mL) for 5 min at komnatnoj temperature, subsequently at peremešivanii dobavlâli ammonium chloride (1.049 g, 19.61 mmol) and DIEA (3.42 ml, 19.61 mmol). Reakcionnuû mix ostavlâli peremešivatʹsâ in komnatnoj temperature within a 1 h. Reakcionnuû vylivali blend in water (100 ml) and ékstragirovali ethyl acetate (3 × 50 ml). Émirats organic layers promyvali water (50 ml), nasyŝennym solevym solution (25 ml), dried over sodium sulfate, and filʹtrovali koncentrirovali. Ostatočnoe quantity DMF udalâli, suspendiruâ maslânistoe tverdoe substance in 100 ml of water and 100 ml of Hexane. The biphasic slurry was vigorously stirred for 30 minutes, filtered and washed with hexane to give 4 - ((1R, 3S) -3-metoksitsiklogeksilamino) -2- (methylthio) pyrimidine-5-carboxamide (1.1081 g, 3.74 mmol, 95% yield) as an off-white solid. MS (ESI) m / z 397,2 [M + 1]⁺.

G. 4 - ((1R, 3S) -3-Metoksiciklogeksilamino) -2- (methylsulfonyl) pyrimidine-5-carboxamide. To a solution of 4 - ((1R, 3S) -3-metoksiciklogeksilamino) -2- (methylthio) pyrimidine-5-carboxamide (1.1081 g, 3.74 mmol) in DCM (18.69 ml) and acetone (18, 69 ml) at a temperature komnatnoj dobavlâli mCPBA (1.676 g, 7.48 mmol) in PÄTU partie week and 2 min at peremešivali komnatnoj temperature in week 16 h. To a mixture of crude reakcionnoj dobavlâli Water 10% Sodium thiosulfate solution (35 ml) and the mixture peremešivali for 5 min before uparivaniem letučih Solvent. Substance worked between ethyl acetate and water, and thereafter Organic layer promyvali nasyŝennym Aquatic sodium bicarbonate solution and then nasyŝennym solevym solution. Émirats vodnye layers promyvali then ethyl acetate (3h), organic layers obʺedinâli, dried over sodium sulphate, and filʹtrovali kondensirovali. After drying under high vacuum to give 4 - ((1R, 3S) -3-metoksitsiklogeksilamino) -2- (methylsulfonyl) pyrimidine-5-carboxamide (0.9887 g, 3.01 mmol, 81% yield) as a white solid . MS (ESI) m / z 329,3 [M + 1]⁺.

H. 4 - ((1R, 3S) -3-Metoksitsiklogeksilamino) -2 - ((1R, 4R) -4-metoksitsiklogeksilamino) pyrimidine-5-carboxamide. To a stirred solution of 4 - ((1R, 3S) -3-metoksitsiklogeksilamino) -2- (methylsulfonyl) pyrimidine-5-carboxamide (0.3 g, 0.914 mmol) and (1R, 4R) -4-metoksitsiklogeksanamina (0.236 g, 1.827 mmol) in DMSO (0.914 mL) was added DIEA (0.637 mL, 3.65 mmol) and the reaction mixture was stirred at 100 ° C for 17 hours. The crude reaction mixture was concentrated and then purified by silica gel chromatography (0-10 % methanol in ethyl acetate). The product fractions were combined and concentrated to give 4 - ((1R, 3S) -3-metoksitsiklogeksilamino) -2 - ((1R, 4R) -4-metoksitsiklogeksilamino) pyrimidine-5-carboxamide (0.155 g, 0.411 mmol, 44.9% yield) as a white solid.¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / 8.95 million. (D, J = 7,42 Hz, 1H), 8.34 (s, 1H), 7,01-7,17 (m, 1H), 6.76-6.88 (m, 1H), 3, 51-4,07 (m, 2H), 2,97-3,29 (m, 8H), 1,63-2,42 (m, 8H), 0,98-1,39 (m, 9H); MS (ESI) m / z 378,4 [M + 1]⁺.

Example 16: 2 - ((1R, 4R) -4-Hydroxy-4-methylcyclohexylamine) -4 - ((1R, 3S) -3-hydroxycyclohexylamino) pyrimidine-5-carboxamide

<img file="00000119.jpg" he="38" wi="57" img-format="tif" img-content="undefined" />

Hydrochloride A. (1R, 4R) -4-Amino-1-methylcyclohexanol.

A solution of (1R, 4R) -4- (dibenzylamino) -1-methylcyclohexanol (15.3 g, 49.4 mmol; prepared as described in International Patent Application PCT WO2010 / 027500) in methanol (137 ml) and ethyl acetate ( 137 mL) in a 500 mL Parr ovom barbatirovaniya degassed by nitrogen through the solution for 5 min. To the solution was added palladium hydroxide on carbon (6.94 g, 4.94 mmol) and the vessel was placed on a Parr shaker for 6 days at 3 atomsferah hydrogen. The vessel was removed from the Parr shaker and the suspension was then filtered through celite. The filtrate was concentrated, the solid residue was dissolved in 50 ml of methanol, acidified with aqueous hydrochloric acid (6 M, 9.06 mL, 54.4 mmol) and concentrated to give the hydrochloride (1R, 4R) -4-amino-1-methylcyclohexanol (8 , 31 g, 50.2 mmol, 101% yield) as an off-white solid,

B. Tert-butyl (1R, 4R) -4-hydroxy-4-metiltsiklogeksilkarbamat. Hydrochloride To a stirred solution of (1R, 4R) -4-amino-1-methylcyclohexanol (8.31 g, 50.2 mmol) in aqueous sodium hydroxide (1N, 100 mL, 100 mmol) was added di-tert-butyl- dicarbonate (13.68 g, 62.7 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and then purified by silica gel chromatography (0-100% ethyl acetate in hexane). The product fractions were combined and concentrated. The substance contained ~ 50% the desired product as indicated by LCMS, so the material re-purified twice on silica gel using 0-50% ethyl acetate in hexane as the mobile phase. The product fractions were combined and concentrated to give tert-butyl (1R, 4R) -4-hydroxy-4-metiltsiklogeksilkarbamata (2.2 g, 9.59 mmol, 19 13% yield) as a white solid. MS (ESI) m / z 230,5 [M + 1]⁺.

C. trifluoroacetate (1R, 4R) -4-amino-1-methylcyclohexanol. To a stirred solution of tert-butyl (1R, 4R) -4-hydroxy-4-metiltsiklogeksilkarbamata (2.04 g, 8.90 mmol) in DCM (44 mL) was added TFA (13.71 mL, 178 mmol) and the solution was stirred at room temperature for 22 hours. The reaction mixture was concentrated, the solid residue was twice triturated with ethyl ether to give the trifluoroacetate (1R, 4R) -4-amino-1-methylcyclohexanol (2.106 g, 8.66 mmol, 97% yield) as a white solid.¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 7.73 (br. S., 3H), 4.39 (br. S., 1H), 3.05 (d, J = 3,51 Hz, 1H), 1,27- 1.97 (m, 8H), 1.11 (s, 3H); MS (ESI) m / z 130,2 [M + 1]⁺.

D. 2 - ((1R, 4R) -4-Hydroxy-4-methylcyclohexylamine) -4 - ((1R, 3S) -3-hydroxycyclohexylamino) pyrimidine-5-carboxamide. To a stirred solution of 4 - ((1R, 3S) -3-hydroxycyclohexylamino) -2- (methylsulfonyl) pyrimidine-5-carboxamide (0.432 g, 1.374 mmol; synthesis described herein) and triflate (1R, 4R) -4- amino-1-methylcyclohexanol (0.435 g, 1.786 mmol) in dioxane (2.75 mL) was added DIEA (0.718 mL, 4.12 mmol) and the resulting solution was stirred at 110 ° C for 23 hours. The crude reaction mixture was concentrated and the solid residue was purified by HPLC (20-100% methanol in water). The product fractions were combined, concentrated, and the solid residue was triturated with acetonitrile. The resulting precipitate was collected to yield 2 - ((1R, 4R) -4-hydroxy-4-methylcyclohexylamine) -4 - ((1R, 3S) -3-hydroxycyclohexylamino) pyrimidine-5-carboxamide (0.0483 g, 0.133 mmol, 9,¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8.91 (d, J = 6,64 Hz, 1H), 8.34 (br. S., 1H), 6,56-7,26 (m, 1H), 3.39 -4.78 (m, 4H), 2.54 (s, 3H), 0,66-2,25 (m, 19H); MS (ESI) m / z 364,5 [M + 1]⁺.

Example 17: 4 - ((1S, 3S, 4S) -3-Gidroksi-4-metiltsiklogeksilamino) -2 - ((1R, 4S) -4-metoksitsiklogeksilamino) pyrimidine-5-carboxamide; 4 - ((1R, 3R, 4R) -3-gidroksi-4-metiltsiklogeksilamino) -2 - ((1R, 4R) -4-metoksitsiklogeksilamino) pyrimidine-5-carboxamide; 4 - ((1S, 3R, 4R) -3-gidroksi-4-metiltsiklogeksilamino) -2 - ((1R, 4S) -4-metoksitsiklogeksilamino) pyrimidine-5-carboxamide; 4 - ((1R, 3S, 4S) -3-gidroksi-4-metiltsiklogeksilamino) -2 - ((1R, 4R) -4-metoksitsiklogeksilamino) pyrimidine-5-carboxamide

<img file="00000120.jpg" he="33" wi="156" img-format="tif" img-content="undefined" />

A. 2 - ((1S, 4S) -4-Hydroxy-4-methylcyclohexyl) isoindoline-1,3-dione. To a stirred solution of (1S, 4S) -4-amino-1-methylcyclohexanol (10 g, 77 mmol; prepared as described in International Patent Application PCT WO2010 / 027500) and potassium carbonate (18.72 g, 135 mmol) in water (155 ml) at 0 ° C was added N-karbetoksiftalid (18.66 g, 85 mmol) and the solution was stirred for 2 hours at room temperature. The fine slurry was filtered, again suspended in 100 ml of water and again filtered to obtain 2 - ((1S, 4S) -4-hydroxy-4-methylcyclohexyl) isoindoline-1,3-dione (11.413 g, 44.0 mmol, 56 , 9% yield) as a white powder.¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 7,79-7,88 (m, 4H), 4.11 (s, 1H), 3.94 (s, 1H), 2.51-2.56 (m, 1H), 2,44-2,49 (m, 1H), 1.56-1.70 (m, 2H), 1.33-1.47 (m, 4H), 1.13 (s, 3H); MS (ESI) m / z 260,5 [M + 1]⁺.

B. 2- (4-methylcyclohex-3-enyl) isoindoline-1,3-dione. 2 - ((1S, 4S) -4-Hydroxy-4-methylcyclohexyl) isoindoline-1,3-dione (4.6568 g, 17.96 mmol) and potassium hydrogensulfate (4.89 g, 35.9 mmol) were combined and heated to 140 ° C for 20 min. No reaction was observed, however, water (11.22 ml) and sulfuric acid (7.66 mL, 144 mmol) and the reaction mixture was heated to 100 ° C for 2 h. The crude suspension was cooled to room temperature and poured into 200 ml of crushed ice / water, stirred vigorously for 30 min, then filtered to give the crude product as a white solid. The white solid was purified by silica gel chromatography (0-10% ethyl acetate in hexanes) and the product fractions were combined and concentrated to give 2- (4-methylcyclohex-3-enyl) isoindoline-1,3-dione (3.33 g , 13.80 mmol, 77% yield) as a white solid. MS (ESI) m / z 242,0 [M + 1]⁺.

C. 4-methylcyclohexyl-3-enamine. To a stirred suspension of 2- (4-methylcyclohex-3-enyl) isoindoline-1,3-dione (5.24 g, 21.72 mmol) in methanol (163 ml) and DCM (54.3 mL) was added hydrazine hydrate ( 3.69 ml, 76 mmol) and the reaction mixture was stirred for 15 hours. to the crude suspension was added 400 mL of water, and the mixture was stirred for 10 minutes, then extracted with DCM (4 × 400 mL). The combined organic layers were dried over sodium sulfate, then concentrated to give 4-methylcyclohex-3-enamine (2.415 g, 21.72 mmol, 100% yield) as a pale yellow oil. MS (ESI) m / z 112,2 [M + 1]⁺.

D. tert-butyl-4-methylcyclohex-3-enilkarbamat. To a stirred solution of 4-methylcyclohex-3-enamine (2.415 g, 21.72 mmol) and TEA (3.33 mL, 23 89 mmol) in DCM (43.4 mL) at 0 ° C was added di-tert-butyl -dikarbonat (7.11 g, 32.6 mmol). The resulting mixture was stirred for 3 days at room temperature. The crude reaction mixture was concentrated, then purified by silica gel chromatography (0-10% ethyl acetate in hexane). The product fractions were combined and concentrated to give tert-butyl-4-methylcyclohex-3-enilkarbamata (1.65 g, 7.81 mmol, 36.0% yield) as a white solid.¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 6.72 (d, J = 7,42 Hz, 1H), 5.26 (br. S., 1H), 3,35-3,49 (m, 1H), 1.66 -2.22 (m, 5H), 1.60 (s, 3H), 1.38 (s, 10H); MS (ESI) m / z 212,4 [M + 1]⁺.

E. Tert-butyl-3-hydroxy-4-metiltsiklogeksilkarbamat. To a stirred solution of tert-butyl-4-methylcyclohex-3-enilkarbamata (1, 5844 g, 7.50 mmol) in THF (94 mL) at 0 ° C was added 1M borane THF complex (33.7 mL, 33.7 mmol ). The solution was stirred at 0 ° C for 1 hour and then at room temperature for 2 hours. The reaction mixture was slowly quenched with water (40.5 mL, 2249 mmol) diluted with ethanol (39.8 mL, 682 mmol) and acidified with aqueous sodium hydroxide solution (5N, 37.5 ml, 187 mmol). To a stirred two-phase mixture was slowly added hydrogen peroxide (38.3 ml, 375 mmol) and the resulting mixture was heated to 45 ° C for 20 hours. The crude reaction mixture was quenched with a saturated aqueous sodium sulfite solution I (70 ml) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with saturated brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (0-100% ethyl acetate in hexane). The product fractions were combined and concentrated to afford a mixture of four isomers of tert-butyl-3-hydroxy-4-metiltsiklogeksilkarbamata (trans arrangement of the 3-hydroxy and 4-methyl group) (0.9608 g, 4.19 mmol, 55.9% yield) as a white solid.¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 6.60-6.85 (m, 1H), 4,29-4,58 (m, 1H), 3,35-3,80 (m, 1H), 2,81-3 28 (m, 1H), 1,20-1,96 (m, 14H), 0,79-1,14 (m, 5H); MS (ESI) m / z 230,5 [M + 1]⁺.

F. 5-Amino hydrochloride (trans) -2-methylcyclohexanol. To a vigorously stirred methanol (10.47 ml) at 0 ° C was added acetyl chloride (0.893 mL, 12.57 mmol). The solution was stirred for 30 min, then tert-butyl-3-hydroxy-4-methylcyclohexyl-carbamate (0.9608 g, 4.19 mmol) and stirring was continued for 22 hours at room temperature. The crude reaction mixture was concentrated, and the solid residue was triturated with ethyl ether (2 × 50 mL) to give hydrochloride of 5-amino- (trans) -2-methylcyclohexanol (0.694 g, 4.19 mmol, 100% yield) as a white solid. MS (ESI) m / z 112,2 [M + 1]⁺.

G. 2- (Trans-4-metoksiciklogeksilamino) -4- (methylsulfinyl) pyrimidine-5-carboxamide. To a solution of 2 - ((1R, 4R) -4-metoksiciklogeksilamino) -4- (methylthio) pyrimidine-5-carboxamide (1.24 g, 4.18 mmol; synthesis are disclosed in the Present Description) in NMP (12.30 mL ) at 0 ° C Porcia dobavlâli mCPBA (0.938 g, 4.18 mmol), and mix reakcionnuû peremešivali in week 1 h at this temperature providing a medlennoe needed to komnatnoj. Reakcionnuû blend razbavlâli water (120 ml), peremešivali for 10 min, and received by Solid substances udalâli via filtration. The filtrate koncentrirovali in vacuo at less than 30 ° C with receipt of 2 - ((1R, 4R) -4-metoksiciklogeksilamino) -4- (methylsulfinyl) pyrimidine-5-carboxamide (1.307 g, 4.18 mmol, 100% output) in see white suspensions in NMP (~ 10 ml). This Syru suspension ispolʹzovali in next Stages at no extra cleaning.⁺.

H. 4 - ((1S, 3S, 4S) -3-Gidroksi-4-metiltsiklogeksilamino) -2 - ((1R, 4S) -4-metoksitsiklogeksilamino) pyrimidine-5-carboxamide, 4 - ((1R, 3R, 4R ) -3-gidroksi-4-metiltsiklogeksilamino) -2 - ((1R, 4R) -4-metoksitsiklogeksilamino) pyrimidine-5-carboxamide, 4 - ((1S, 3R, 4R) -3-gidroksi-4-metiltsiklogeksilamino) - 2 - ((1R, 4S) -4-metoksitsiklogeksilamino) pyrimidine-5-carboxamide, 4 - ((1R, 3S, 4S) -3-gidroksi-4-metiltsiklogeksilamino) -2 - ((1R, 4R) -4- metoksitsiklogeksilamino) pyrimidine-5-carboxamide. K sыroy reactionary mixtures (2 - ((1R, 4R) -4-metoksitsiklogeksilamino) -4- (metilsulyfinil) pyrimidine-5-carboxamide (1.31 g, 4.19 mmoly) in NMP (10 ml) dobavlyali sыroy gidrohlorid 5 -amino- (trans) -2-metiltsiklogeksanola (0.695 g, 4.19 mmoly) in he saw simply entails in NMP (15,00 ml). K suspensions dobavlyali DIЭA (3.65 mL, 20.97 mmoly) and reaktsionnuyu smesy Heat to 100 ° C for 46 h. NMP manure removal uparivaniem at 70 ° C, the solid residue was diluted with DCM and purified by silica gel chromatography (0-15% methanol in DCM). The product fractions were combined, concentrated, and then re-purified by chromatography on silica gel (0-10% methanol in DCM). The product fractions were combined and concentrated to give a mixture of four products (two diastereomers and their respective enantiomers (1.665 g) NMR mixture.:¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8.35 (d, J = 5,45 Hz, 1H), 4,50-4,71 (m, 1H), 4.34 (br. S., 1H), 3.53 -3.69 (m, 1H), 3.23 (s, 3H), 3.03-3.19 (m, 2H), 1,77-2,09 (m, 5H), 1.65 (br .. s, 1H), 1,07-1,39 (m, 13H), 0.94 (d, J = 6,49 Hz, 3H); MS (ESI) m / z 378,0 [M + 1]⁺. The crude material was separated by chiral SFC, using AD-H column, to afford compounds 4, labeled as Peak 1 Peak 4, PIC 1 wherein the first compound eluted and 4, PIC is the last eluted compound. The stereochemistry of peaks 1-4 was determined by methods known to those skilled in the art.

Peak 1: 4 - ((1S, 3S, 4S) -3-Hydroxy-4-methylcyclohexylamine) -2 - ((1R, 4S) -4-metoksitsiklogeksilamino) pyrimidine-5-carboxamide. 0 3482 g, 0.922 mmol, 22% yield.¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8.88 (d, J = 6,64 Hz, 1H), 8.34 (br. S., 1H), 7.07 (d, J = 7,03 Hz, 1H), 4.58 (d, J = 5,08 Hz, 1H), 4.10 (q, J = 5,08 Hz, 1H), 3,51-3,92 (m, 1H), 3.44 (dd , J = 7.03, 5.08 Hz, 1H), 3.23 (s, 3H), 3.17 (d, J = 5,47 Hz, 3H), 3.09 (br. s., 1H ), 2.98 (br. s., 1H), 2.55 (d, J = 7.03 Hz, 1H), 1,77-2,23 (m, 5H), 1.66 (d, J = 12.49 Hz, 1H), 1,04-1,35 (m, 6H), 0.94 (d, J = 5,86 Hz, 3H).

PIC 2: 4 - ((1R, 3R, 4R) -3-hydroxy-4-methylcyclohexylamine) -2 - ((1R, 4R) -4-metoksitsiklogeksilamino) pyrimidine-5-carboxamide. 0.4146 g, 1.098 mmol, 26.2% yield.¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8.88 (d, J = 6,25 Hz, 1H), 8.34 (br. S., 1H), 7.07 (d, J = 7,03 Hz, 1H), 4.57 (br. s., 1H), 4.11 (br. s., 1H), 3,50-3,67 (m, 1H), 3.23 (s, 2H), 3.17 ( br. s., 2H), 3.03-3.13 (m, 1H), 2.94-3.02 (m, 1H), 2.89 (q, J = 7,16 Hz, 4H), 1,60-2,22 (m, 4H), 0,87-1,37 (m, 13H).

PIC 3: 4 - ((1S, 3R, 4R) -3-hydroxy-4-methylcyclohexylamine) -2 - ((1R, 4R) -4-metoksitsiklogeksilamino) pyrimidine-5-carboxamide. 0.3145 g, 0 833 mmol, 19.9% ​​yield.¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 9.25 (d, J = 7,42 Hz, 1H), 8.35 (br. S., 1H), 7.05 (d, J = 6,64 Hz, 1H), 6,76-6,92 (m, 1H), 4.53 (d, J = 3,90 Hz, 1H), 4.32 (br. s., 1H), 4.03-4.17 (m , 1H), 3,52-3,84 (m, 1H), 3.40-3.50 (m, 1H), 3.13-3.26 (m, 4H), 3.00-3.12 (m, 1H), 1,77-2,12 (m, 5H), 1,10-1,69 (m, 9H), 0.94 (d, J = 6,64 Hz, 3H).

PIC 4: 4 - ((1R, 3S, 4S) -3-hydroxy-4-methylcyclohexylamine) -2 - ((1R, 4R) -4-metoksitsiklogeksilamino) pyrimidine-5-carboxamide. 0.4715 g, 1.249 mmol, 29.8% yield.¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 9,46-9,75 (m, 1H), 8.35 (s, 1H), 4.57 (br. S., 1H), 4.35 (br. S., 1H ), 3.60-3.79 (m, 1H), 3.23 (s, 4H), 3.00-3.15 (m, 1H), 2.87-2.99 (m, 1H), 1,75-2,06 (m, 5H), 1,06-1,73 (m, 11H), 0.94 (d, J = 6,25 Hz, 3H).

Example 18: 4 - ((1R, 3S) -3-Gidroksiciklogeksilamino) -2 - ((1R, 4R) -4-metoksiciklogeksilamino) pyrimidine-5-carboxamide

<img file="00000121.jpg" he="37" wi="57" img-format="tif" img-content="undefined" />

A. 2-cyclohex-2-enyl-isoindole-1,3-dione. To a solution of 3-bromocyclohexene (500 g, 3.12 mmol) was added potassium phthalimide (580 g, 3.12 mmol) in DMF (2000 ml) and the reaction mixture was stirred at room temperature for 30 hours. The reaction mixture was diluted with water ( 1000 ml), extracted with ethyl acetate (3 times) and the combined organic layers were concentrated to give 2-cyclohex-2-enyl-isoindole-1,3-dione (520 g, 2.30 mol) as a gray solid.

B. 2- (2-Bromo-3-hydroxycyclohexyl) -isoindole-1,3-dione. 2-cyclohexyl-2-enyl-isoindole-1,3-dione (520 g, 2.30 mol) and N-bromosuccinimide (416 g, 2.35 mol) was stirred in a cosolvent chloroform (3000 ml) and ethanol (120 ml ) and stirred at room temperature for 16 hours. When HPLC showed consumption of starting material, the reaction mixture was concentrated to give a solid residue which was diluted hydrochloride solution (450 mL, 2.0 mol) and THF (2000 mL) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give crude product. The crude product was washed with ethanol (2X) to give 2- (2-bromo-3-hydroxy-cyclohexyl) -isoindole-1,3-dione (400 g, 1.23 mol) as a white solid.¹Н-ЯМР (CD₃OD, 400 MHz): δ h / million 7.87 (m, 4H), 4.70 (m, 1H), 4.33 (m, 1H), 3.70 (m, 1H), 2.15. (m, 2H), 1.88 (m, 2H), 1.53 (m, 2H).

C. 2- (3-hydroxycyclohexyl) -isoindole-1,3-dione. To a stirred solution of 2- (2-bromo-3-hydroxy-cyclohexyl) -isoindole-1,3-dione (400 g, 1.23 mol) and 2,2'-azobis (2-methylpropionitrile) (20 g) in toluene (4000 ml) and methanol (400 ml) was added tri-n-butyltin hydride (430 g, 1.48 mol) and the reaction mixture was stirred at 80 ° C for 64 hours. The reaction mixture was concentrated to give crude product. The crude product was washed with petroleum ether and ethyl acetate (1: 1) to give 2- (3-hydroxycyclohexyl) -isoindole-1,3-dione (240 g, 0.98 mol) as a white solid.¹Н-ЯМР (CD₃OD, 400 MHz): δ h / million 7.82 (m, 4H), 4.16 (m, 1H), 3.63 (m, 1H), 2.13 (m, 2H), 1.98. (d, 2H), 1.89 (m, 1H), 1.68 (t, 1H), 1.46 (m, 1H), 1.31 (m, 1H).

D. (1S, 3R) -2- (3-hydroxycyclohexyl) -isoindole-1,3-dione and (1R, 3S) 3- (1,3-dioxo-1,3-dihydroisoindol-2-yl) cyclohexyl acetate acid. A solution of 2- (3-hydroxy-cyclohexyl) -isoindole-1,3-dione (240 g, 0.98 mol) and lipase (87 g) in THF (3000 ml) was stirred at room temperature under nitrogen for 1? 2 hours. Then, to the solution was added vinyl acetate (252 g, 2.88 mol) and the reaction mixture was stirred at rt. temp, for 3 ~ 5 hours. The reaction mixture was filtered and the filtrate was concentrated to give crude product. The crude product was purified on silica gel (eluting with petroleum ether / ethyl acetate = 10: 1) to give (1S, 3R) -2- (3-hydroxycyclohexyl) -isoindole-1,3-dione (R_f= 0.6, petroleum ether / ethyl acetate = 3/1, 90 g, 0.37 mol, yield: 39%) as a white solid. ¹Н-ЯМР (CD₃OD, 400 MHz): δ h / million 7.82 (m, 4H), 4.16 (m, 1H), 3.63 (m, 1H), 2.13 (m, 2H), 1.98. (m, 2H), 1.89 (m, 1H), 1.68 (m, 1H), 1.46 (m, 1H), 1.31 (m, 1H). (1R, 3S) 3- (1,3-dioxo-1,3-dihydroisoindol-2-yl) cyclohexyl ester (R_f= 0.2, petroleum ether / ethyl acetate = 3/1, 110 g, 0.38 mol, yield: 39%) as a white solid. ¹Н-ЯМР (CD₃OD, 400 MHz): δ h / million 7.83 (m, 4H), 4.78 (m, 1H), 4.23 (m, 1H), 2.33 (m, 2H), 2.13. (m, 2H), 2.07 (m, 5H), 1.95 (m, 1H), 1.74 (m, 1H), 1.46 (m, 1H).

E. (1S, 3R) -3-aminocyclohexanol. To a solution of (1S, 3R) -2- (3-hydroxycyclohexyl) -isoindole-1,3-dione (90 g, 0.37 mol) was added hydrazine (90 g, 1.8 mol) in ethanol (1500 ml) and the reaction solution was stirred at 100 ° C for 3 hours. The reaction solution was filtered, and the filtrate was concentrated to afford (1S, 3R) -3-aminocyclohexanol (25 g, 0.21 mmol) as a yellow solid.¹Н-ЯМР (CD₃OD, 400 MHz) δ hr. / Million 3.54 (m, 1H), 2.65 (m, 1H), 2.12 (m, 1H), 1.92 (m, 1H), 1.89 ( m, 2H), 1.32 (m, 1H), 1.06 (m, 2H).

F. Ethyl 4 - ((1R, 3S) -3-hydroxycyclohexylamino) -2- (methylthio) pyrimidine-5-carboxylate. To a stirred solution of ethyl 4-chloro-2- (methylthio) pyrimidine-5-carboxylate (4.38 g, 18.82 mmol) and (1S, 3R) -3-aminocyclohexanol (2.276 g, 19.76 mmol) in ethanol (75 mL) was added DIEA (4.93 mL, 28.2 mmol). The reaction mixture was heated to 60 ° C for 2 hours, cooled and concentrated, then purified by silica gel chromatography (20-100% ethyl acetate / hexane). Appropriate fractions were combined and concentrated to give ethyl 4 - ((1R, 3S) -3-hydroxycyclohexylamino) -2- (methylthio) pyrimidine-5-carboxylate (5 g, 16.06 mmol, 85% yield) as a white foam. MS (ESI) m / z 312,1 [M + 1]⁺.

G. 4 - ((1R, 3S) -3-hydroxycyclohexylamino) -2- (methylthio) pyrimidine-5-carboxylic acid. To a stirred solution of ethyl 4 - ((1R, 3S) -3-hydroxycyclohexylamino) -2- (methylthio) pyrimidine-5-carboxylate (5 g, 16.06 mmol) in ethanol (50 ml) was added 2M sodium hydroxide (20 mL, 40.0 mmol). Stirring was continued at room temperature for 1 h. The reaction mixture was neutralized by adding a saturated citric acid. The resulting precipitate was filtered and dried to give 4 - ((1R, 3S) -3-hydroxycyclohexylamino) -2- (methylthio) pyrimidine-5-carboxylic acid (4.5 g, 15.88 mmol, 99% yield) as a white solid.¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 13.21 (br. S., 1H), 8,44-8,54 (m, 2H), 4.74 (d, J = 3,90 Hz, 1H), 3.97 -4.12 (m, 1H), 3.56 (d, J = 3,12 Hz, 1H), 2.46 (s, 3H), 2.05-2.16 (m, 1H), 1, 84 (d, J = 10,15 Hz, 1H), 1.65-1.80 (m, 2H), 1,11-1,36 (m, 4H). MS (ESI) m / z 284,1 [M + 1]⁺.

H. 4 - ((1R, 3S) -3-Gidroksiciklogeksilamino) -2- (methylthio) pyrimidine-5-carboxamide. 4 - ((1R, 3S) -3-gidroksiciklogeksilamino) -2- (methylthio) pyrimidine-5-karbonovuû acid (4.5 g, 15.88 mmol) and HATU (9.06 g, 23.82 mmol) rastvorâli in DMF (75 mL) and peremešivali for 5 min at temperature before the addition of komnatnoj Ammonium chloride (4.25 g, 79 mmol) and DIEA (13.87 ml, 79 mmol). Reakcionnaâ mix stanovilasʹ želtoj in additions grounds. Reakcionnuû mix ostavlâli peremešivatʹsâ in komnatnoj temperature in week 1 h, then worked between water and ethyl acetate. Organic layer promyvali í ç nasyŝennym solevym solution, then dried over sodium sulfate, and filʹtrovali koncentrirovali with receipt of 4 - ((1R, 3S) -3-gidroksiciklogeksilamino) -2- (methylthio) pyrimidine-5-carboxamide (4.19 g, 14.84 mmol, yield 93%) as an off-white solid. MS (ESI) m / z 283,2 [M + 1]⁺.

I. 4 - ((1R, 3S) -3-hydroxycyclohexylamino) -2- (methylsulfonyl) pyrimidine-5-carboxamide. To a stirred suspension of 4 - ((1R, 3S) -3-hydroxycyclohexylamino) -2- (methylthio) pyrimidine-5-carboxamide (302 mg, 1.070 mmol) in DCM (10 ml) and acetone (10 ml) was added 3-chloroperoxybenzoic acid (479 mg, 2.139 mmol). The reaction mixture was stirred at room temperature for 1.5 hours. The crude reaction mixture was quenched by adding 10 ml of a 10% solution of sodium thiosulfate, stirred for 5 minutes then partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate and brine. The combined aqueous layers were extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to afford 4 - ((1R, 3S) -3-hydroxycyclohexylamino) -2- (methylsulfonyl) pyrimidine-5-carboxamide (259 mg, 0.824 mmol, 77% yield) as a white solid. MS (ESI) m / z 315,2 [M + 1]⁺.

J. 4 - ((1R, 3S) -3-hydroxycyclohexylamino) -2 - ((1R, 4R) -4-metoksitsiklogeksilamino) pyrimidine-5-carboxamide. To a stirred solution of 4 - ((1R, 3S) -3-hydroxycyclohexylamino) -2- (methylsulfonyl) pyrimidine-5-carboxamide (0.178 g, 0.566 mmol) and (1R, 4R) -4-metoksitsiklogeksanamin (0.146 g, 1.132 mmol ) in DMSO (1.132 mL) was added DIEA (0.395 mL, 2.265 mmol). The reaction mixture was stirred at 100 ° C for 17 hours. The crude reaction mixture was concentrated and purified by silica gel chromatography (0-15% methanol / ethyl acetate). The product fractions were combined and concentrated to give 4 - ((1R, 3S) -3-hydroxycyclohexylamino) -2 - ((1R, 4R) -4-metoksitsiklogeksilamino) pyrimidine-5-carboxamide (0.08 g, 0.220 mmol, 38 9% yield) as a light brown solid.¹H-ЯМР (CD₃OD, 400 MHz):. Δ h / million 8.29 (s, 1H), 3,99-4,04 (m, 1H), 3.76 (m, 1H), 3.50-3.63 ( m, 1H), 3.37 (s, 3H), 3.24 (m, 1H), 3.23 (m, 1H), 1,92-2,12 (m, 6H), 1,83-1 87 (m, 1H), 1,19-1,41 (m, 8H). MS (ESI) m / z 364,6 [M + 1]⁺.

Example 19: 4 - ((1R, 3S) -3-Gidroksitsiklogeptilamino) -2 - ((1R, 4R) -4-metoksitsiklogeksilamino) pyrimidine-5-carbonitrile

<img file="00000122.jpg" he="33" wi="59" img-format="tif" img-content="undefined" />

A. 4-Chloro-2 - ((1R, 4R) -4-metoksitsiklogeksilamino) -pyrimidine-5-carbonitrile. (1R, 4R) -4-Metoksitsiklogeksanamin (6.37 g, 49.3 mmol), 2,4-dichloropyrimidine-5-carbonitrile (6 g, 34.5 mmol) and DIEA (9.03 mL, 51.7 mmol) was stirred in THF (180 mL) at -10 ° C (salt ice bath) and stirred at the same temperature for 5 hours. the reaction mixture was further stirred overnight while the temperature slowly rose to room temperature. Analysis of the reaction mixture by LC / MS showed formation of products with a ratio of about 3: 7. The reaction mixture was concentrated under reduced pressure, diluted with water (100 ml) and extracted with ethyl acetate (2x). The combined organic layers were washed with water and saturated brine and dried over magnesium sulfate. Agent for drying was removed by filtration and the solution concentrated.¹H-ЯМР (ДМСО-d₆, 400 MHz): δ h / million 8.74 (d, J = 8,2 Hz, 1H), 8,60-8,72 (m, 1H), 3,58-3,80 (m, 1H. ), 3.18 (d, J = 2,0 Hz, 3H), 2.97-3.12 (m, 1H), 1.96 (d, J = 10,9 Hz, 2H), 1.83 (d, J = 10,5 Hz, 2H), 1.21-1.39 (m, 2H), 1,06-1,22 (m, 2H); MS (ES) m / z 267,2 [M + 1]⁺) As a white solid and 2-chloro-4 - ((1R, 4R) -4-metoksitsiklogeksilamino) -pyrimidine-5-carbonitrile (2.5 g, 9.37 mmol, 27.2% yield; ¹H-ЯМР (ДМСО-d₆, 400 MHz):. Δ h / million 8.50 (s, 1H), 8.31 (d, J = 7,8 Hz, 1H), 3.90 (dtd, J = 11.6, 7.6 , 4.1 Hz, 1H), 3.19 (s, 3H), 2.98-3.10 (m, 1H), 1.98 (d, J = 10,5 Hz, 2H), 1.77 (d, J = 11,3 Hz, 2H), 1,36-1,54 (m, 2H), 1,05-1,22 (m, 2H). MS (ES) m / z 267,1 [M + 1]⁺) As a white solid.

Regiochemistry separated isomers was confirmed by the following experiments:

4-Chloro-2 - ((1R, 4R) -4-metoksitsiklogeksilamino) -pyrimidine-5-carbonitrile (50 mg, 0.187 mmol), diatsetoksipallady (42.1 mg, 0.187 mmol) and ammonium formate (59.1 mg, 0.937 mmol) in methanol (1 ml) was stirred at 70 ° C for 2 hours. The reaction mixture was cooled to room temperature and filtered through a pad of celite. The resulting solution was concentrated and subjected to flash homatografii (0-15% methanol in DCM) to give 2 - ((1R, 4R) -4-metoksitsiklogeksilamino) -pyrimidine-5-carbonitrile as a white solid.¹Н-ЯМР (ie ДМСО₆, 400 MHz; measured at room temperature):. δ h / million 8.66 (d, J = 2.7 Hz, 1H), 8.59 (d, J = 3.1 Hz, 1H), 8.22 (d, J = 8.2 Hz, 1H), 3.62-3.77 (m, 1H), 3.18 (s, 3H), 2.99-3.12 (m, 1H), 1,90-2, 02 (m, 2H), 1.84 (d, J = 10,5 Hz, 2H), 1.21-1.37 (m, 2H), 1,06-1,21 (m, 2H).

¹Н-ЯМР (ie ДМСО₆, 400 MHz; measured at 80 ° C):... δ h / million 8.57 (br s, 1H), 7.91 (d, J = 7,0 Hz, 1H), 3,68-3,85 (m, 1H), 3.05-3.16 (m, 1H), 3.02 (s, 3H), 1.92-2.05 (m, 2H), 1.87 (d, J = 10,2 Hz , 2H), 1.26-1.41 (m, 2H), 1,11-1,26 (m, 2H).

The same method described above was used for 2-chloro-4 - ((1R, 4R) -4-metoksitsiklogeksilamino) -pyrimidine-5-carbonitrile to give 4 - ((1R, 4R) -4-metoksitsiklogeksilamino) pyrimidin-5- carbonitrile as a white solid. ¹Н-ЯМР (ie ДМСО₆, 400 MHz; measured at room temperature):. δ h / million 8.56 (d, J = 15,2 Hz, 1H), 7,74-7,91 (m, 1H), 3,86-4,11 (m, 2H), 3.19 (s, 3H), 3.12 (d, J = 5.1 Hz, 1H), 1.92-2.04 (m, 2H), 1.78 (d, J = 10 , 5 Hz, 2H), 1.35-1.52 (m, 2H), 1.05-1.18 (m, 2H).¹H-ЯМР (ДМСО-d₆, 400 MHz; measured at 80 ° C):. δ h / million 8.53 (d, J = 28,1 Hz, 1H), 7.47 (br s, 1H), 3,93-4,08 (m.,. 1H), 3.16 (d, J = 5,5 Hz, 1H), 1,91-2,07 (m, 2H), 1.84 (d, J = 10,5 Hz, 2H), 1, 37-1,54 (m, 2H), 1.10-1.21 (m, 2H).

B. hydrochloride (1S, 3R) -3-aminotsiklogeptanola. To a vigorously stirred methanol (60 ml) at 0 ° C was added acetyl chloride (5.11 mL, 72.0 mmol) and the resulting mixture was allowed to stir for 30 min. Tert-butyl (1R, 3S) -3-gidroksitsiklogeptilkarbamat (5500 mg, 23.98 mmol; synthesis described herein) and the resulting mixture was then stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to an oil which was triturated with ethyl ether (100 ml) overnight. The solids were filtered, washed with diethyl ether and dried under reduced pressure for several hours to give the hydrochloride (1S, 3R) -3-aminotsiklogeptanola (3780 mg, 22.82 mmol, 95% yield) as a white solid.¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 7.85 (br. S., 3H), 4.69 (d, J = 7,42 Hz, 1H), 3.64 (t, J = 8,79 Hz, 1H), 3,07-3,21 (m, 1H), 2.05 (d, J = 12,89 Hz, 1H), 1,69-1,94 (m, 2H), 1,28-1,68 ( m, 7H). MS (ESI) m / z 130,1 [M + 1]⁺.

C. 4 - ((1R, 3S) -3-Gidroksitsiklogeptilamino) -2 - ((1R, 4R) -4-metoksitsiklogeksilamino) -pyrimidine-5-carbonitrile. To a stirred solution of 4-chloro-2 - ((1R, 4R) -4-metoksitsiklogeksilamino) -pyrimidine-5-carbonitrile (200 mg, 0.750 mmol) and hydrochloride (1S, 3R) -3-aminotsiklogeptanola (186 mg, 1.125 mmol) in DMF (4 mL) was added DIEA (0.458 mL, 2.62 mmol). The resulting mixture was stirred at 70 ° C for 4 hours and then allowed to cool to ambient temperature overnight. DMF was removed under reduced pressure and the residual solid was purified using chromatography on silica gel (0-50% ethyl acetate + 10% 7N ammonia in methanol in hexanes) to give 4 - ((1R, 3S) -3-gidroksitsiklogeptilamino) -2- ((1R, 4R) -4-metoksitsiklogeksilamino) -pyrimidine-5-carbonitrile (210 mg, 0.584 mmol, 78% yield).¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8,07-8,23 (m, 1H), 7,06-7,61 (m, 2H), 4,49-4,63 (m, 1H), 4,00-4 27 (m, 1H), 3,55-3,82 (m, 2H), 3.23 (s, 3H), 3.00-3.16 (m, 1H), 1,07-2,08 (m, 18H). MS (ESI) m / z 360,5 [M + 1]⁺.

Example 20: 2 - ((1R, 4R) -4-Эtoksitsiklogeksilamino) -4 - ((1R, 3S) -3-gidroksi-3-metiltsiklogeksilamino) pyrimidine-5-carbonitrile

<img file="00000123.jpg" he="32" wi="63" img-format="tif" img-content="undefined" />

A. (1R, 4R) -4- (trityl-amino) -cyclohexanol. To a cooled (0 ° C) solution of (1R, 4R) -4-aminocyclohexanol (10 g, 87 mmol) in DCM (250 mL) and TEA (11.2 g, 112 mmol) was added trityl chloride (24.2 g, 87 mmol). The resulting mixture was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate was added to quench the reaction, and the aqueous layer was extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate. Filtration and concentration in vacuo gave a crude product which was purified by chromatography on a silica gel column (50% ethyl acetate in DCM) to give the compound of the title (24.8 g, 70 mmol, 80% yield) as a white solid . MS (ESI) m / z 243,2 [M - 4-aminocyclohexanol]⁺.

B. (1R, 4R) -4-Ethoxy-N-tritiltsiklogeksanamin. To a cooled (0 ° C) solution of (1R, 4R) -4- (trityl-amino) -cyclohexanol (15.0 g, 42 mmol) in DMF (100 ml) was added sodium hydride (3.4 g, 84 mmol, 60% in mineral oil) and ethyl iodide (7.2 g, 46 mmol) at 0 ° C. The resulting mixture was stirred at room temperature overnight under nitrogen. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the aqueous layer was extracted with ethyl acetate. The combined extracts were washed with saturated brine and dried over anhydrous sodium sulfate. Filtration and concentration in vacuo gave a crude product which was purified by chromatography on a silica gel column (5% ethyl acetate in petroleum ether) to give the compound of the title (11.9 g, 31 mmol, 79% yield) as a white solid.¹Н-ЯМР (400 МГц, CDCl₃) Δ hr. / Million 7,56-7,54 (m, 6H), 7.27-7.20 (m, 6H), 7,18-7,14 (m, 3H), 3,42-3 38 (q, 2H), 3,09-3,04 (m, 1H), 2,25-2,21 (m, 1H), 1,80-1,78 (m, 2H), 1.38 (s, 1H), 1,27-1,25 (m, 2H), 1.10 (t, J = 7,2 Hz, 3H), 1.01-0.88 (m, 4H); MS (ESI) m / z 243,2 [M-4-etoksitsiklogeksanamin]⁺.

C. (1R, 4R) -4-Etoksitsiklogeksanamin. To a cooled (0 ° C) solution of (1R, 4R) -4-ethoxy-N-tritiltsiklogeksanamina (13.1 g, 34 mmol) in DCM (10 mL) was added trifluoroacetic acid (18 ml) at 0 ° C. The resulting mixture was dark red. Was added triethylsilane (5 mL) prior to bleaching the resulting mixture. The reaction mixture was stirred at 0 ° C an additional 15 minutes. After removal of all volatiles in vacuo, the solid residue was further dried under high vacuum for 2 h to give the crude product as a white solid. The crude product was dissolved in ethyl acetate and aqueous hydrochloride solution (150 mL, 0.25 mol / l). The organic layer was removed, and the aqueous layer was washed twice with ethyl acetate. Concentration of the aqueous layer in a high vacuum yielded the crude hydrochloride salt of the title amine (6.1 g, 34 mmol, 100% yield) as a white solid, which was used in the next step without further purification. MS (ESI) m / z 144,0 [M + H]⁺.

D. 4-Chloro-2 - ((1R, 4R) -4-etoksitsiklogeksilamino) -pyrimidine-5-carbonitrile. To a cooled (-60 ° C) solution of (1R, 4R) -4-etoksitsiklogeksanamina (6.82 g, 37.9 mmol) and 2,4-dichloropyrimidine-5-carbonitrile (6 g, 34.5 mmol) in THF (115 ml) was added dropwise DIEA (15.02 ml, 86 mmol). The resulting mixture was stirred at -60 ° C for 1 hour and then allowed to warm to room temperature overnight. The resulting mixture was concentrated, and the solid residue was purified by chromatography on a silica gel column (14% ethyl acetate in petroleum ether). The product fractions were combined and concentrated to give 2-chloro-4 - ((1R, 4R) -4-etoksitsiklogeksilamino) -pyrimidine-5-carbonitrile (3.33 g, 11.86 mmol, 34.4% yield) and 4-chloro -2 - ((1R, 4R) -4-etoksitsiklogeksilamino) -pyrimidine-5-carbonitrile (5.5 g, 19.59 mmol, 56.8% yield;¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8,62-8,87 (m, 2H), 3,61-3,86 (m, 1H), 3.44 (dd, J = 7.03, 2.34 Hz, 2H ), 3.12-3.26 (m, 1H), 1,75-2,15 (m, 4H), 1,13-1,44 (m, 4H), 1.08 (td, J = 6 93, 1.76 Hz, 3H); MS (ESI) m / z 281,1 [M + 1]⁺) As a white solid. Major isomer regiochemistry was confirmed by comparison with the proton spectrum of 4-chloro-2 - ((1R, 4R) -4-metoksitsiklogeksilamino) -pyrimidine-5-carbonitrile (synthesis described herein).

E. (1S, 3R) -3- (Dibenzylamino) cyclohexanol. To a suspension of (1S, 3R) -3-aminocyclohexanol (5 g, 43.4 mmol; prepared as described in Tetrahedron: Asymmetry 15 (2004) 2051-2056) and sodium bicarbonate (12.03 g, 143 mmol) in ethanol ( 100 ml) was added (chloromethyl) benzene (15.01 mL, 130 mmol) at room temperature. The reaction mixture was heated at 75 ° C overnight. After completion of the reaction as indicated by LCMS and TLC, the reaction mixture was filtered and the filtrate was concentrated. The solid residue was then dissolved in DCM (250 mL) and washed with aqueous sodium hydroxide (1N, 2 × 100 ml) and saturated brine (2 × 100 mL). The combined organic layers were dried over anhydrous magnesium sulfate, concentrated and purified by silica gel chromatography (0% -80% ethyl acetate in hexane) to yield (1S, 3R) -3- (dibenzylamino) cyclohexanol (11.70 g,¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 7.26-7.37 (m, 8H), 7.17-7.22 (m, 2H), 4.56 (d, J = 4,30 Hz, 1H), 3, 57 (s, 4H), 3.16-3.26 (m, 1H), 2.41 (tt, J = 3.17, 11.86 Hz, 1H), 1.99-2.06 (m, 1H), 1.72 (d, J = 8,20 Hz, 2H), 1.63-1.69 (m, 1H), 1.18-1.28 (m, 2H), 0.98 (t , 2H); MS (ESI) m / z 296,4 [M + 1]⁺.

F. (R) -3- (Dibenzylamino) cyclohexanone. Oxalyl chloride (3.81 mL, 43.6 mmol) was dissolved in dry DCM (150 mL) and cooled to -78 ° C. The reaction mixture was added dropwise DMSO (6.75 mL, 95.0 mmol) in dry DCM (20 ml) and the reaction mixture was stirred for 15 minutes at -78 ° C. They were then added dropwise (1S, 3R) -3- (dibenzylamino) cyclohexanol (11.7 g, 39.6 mmol) in dry DCM (100 ml) using an auxiliary funnel, and the reaction mixture was stirred at -78 ° C for 15 minutes. Was added TEA (27.6 mL, 198 mmol) and the reaction mixture was stirred at -78 ° C for 1 hour. The dry ice bath was removed and the reaction mixture was allowed to warm at room temperature and stirred overnight. The reaction mixture was washed with saturated brine (5 × 500 mL), the organic layer was separated,¹H-NMR (400 MHz, DMSO-d₆) Δ h. / M 7,26-7,39 (m, 8N), 7,17-7,25 (m, 2H), 3,56-3,70 (m, 4H), 2,71-2 81 (m, 1 H), 2,60-2,69 (m, 1H), 2,25-2,42 (m, 2H), 2,04-2,11 (m, 1H), 1.88 -1.99 (m, 2H), 1,69-1,82 (m, 1H), 1,18-1,33 (m, 1H); MS (ESI) m / z 294,4 [M + 1]⁺.

G. (3R, 5R) -N, N-Dibenzyl-1-oxaspiro [2.5] octane-5-amine and (3S, 5R) -N, N-dibenzyl-1-oxaspiro [2.5] octane-5-amine. To the yellow solution of (R) -3- (dibenzylamino) cyclohexanone (10.2 g, 34.8 mmol) and trimethylsulfonium iodide (14.90 g, 73.0 mmol) in dry DMSO (260 ml) was added portionwise tert-butoxide sodium (6.68 g, 69.5 mmol) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight under nitrogen. After completion of the reaction as indicated by LCMS and TLC, the reaction mixture was quenched with 1 L of water and extracted with ethyl acetate (2 × 800 mL). The organic phase was dried over sodium sulfate, concentrated and dried to yield a mixture of (3R, 5R) -N, N-dibenzyl-1-oxaspiro [2.5] octan-5-amine and (3S, 5R) -N, N-dibenzyl-1 -oksaspiro [2.5] octan-5-amine (10.6 g, 99%) as a yellow solid. The mixture was used as such in the next step without further purification. MS (ESI) m / z 308,4 [M + 1]⁺.

H. (1R, 3R) -3- (dibenzylamino) -1-methylcyclohexanol and (1S, 3R) -3- (dibenzylamino) -1-methylcyclohexanol. To a solid mixture of lithium aluminum hydride (95% LAH, 3,47 g, 87 mmol) in THF (230 mL) was slowly added to the clear pale yellow solution above described mixture of (3R, 5R) -N, N-dibenzyl-1- oxaspiro [2.5] octan-5-amine and (3S, 5R) -N, N-dibenzyl-1-oxaspiro [2.5] octane-5-amine (10.69 g, 34.8 mmol) in THF (230 ml) at 0 ° C under a nitrogen atmosphere. The reaction temperature was raised to room temperature and then heated at 65 ° C overnight under a nitrogen atmosphere. After completion of the reaction as indicated by LCMS and TLC, the reaction mixture was transferred to a round bottom flask and then diluted with THF (100 mL), cooled to 0 ° C and with stirring was added dropwise a saturated aqueous sodium sulfate solution to until the reaction the mixture ceased to bubble. The mixture was stirred overnight at room temperature and then filtered through Celite into a flask roughly fused to a round bottom flask. Filtered cake was washed thoroughly with THF and the colorless filtrate was concentrated under reduced pressure. The resulting crude mixture was purified by chromatography on silica gel (0% -60% ethyl acetate in hexane) to give the fast eluting isomer (1R, 3R) -3- (dibenzylamino) -1-methylcyclohexanol (5.5 g, 50%;¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 7.25-7.36 (m, 8H), 7.15-7.21 (m, 2H), 3.85 (s, 1H), 3.55 (s, 4H), 2.86 (tt, J = 3.37, 12.06 Hz, 1H), 1.70-1.81 (m, 2H), 1.38-1.49 (m, 3H), 1.32 ( t, J = 12,30 Hz, 1H), 1,15-1,27 (m, 2H), 1.12 (s, 3H); MS (ESI) m / z 310,4 [M + 1]⁺) As a white solid and then slowly eluting isomer (1S, 3R) -3- (dibenzylamino) -1-methylcyclohexanol (5.1 g, 47%; ¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 7.26-7.36 (m, 8H), 7.16-7.23 (m, 2H), 4.38 (s, 1H), 3,49-3,63 (m , 4H), 2.46 (d, J = 8,98 Hz, 1H), 1.67-1.80 (m, 2H), 1.59 (d, J = 9,76 Hz, 1H), 1 , 33-1,47 (m, 2H), 1.17-1.30 (m, 2H), 0,98-1,13 (m, 1H), 0.89 (s, 3H); MS (ESI) m / z 310,4 [M + 1]⁺) As a thick yellow oil. Experiment COSY and NMR data¹H-NMR, above, was used to verify regiochemistry aminoalcohols. For slowly eluted isomer NOE (by NOESY experiments) were observed between the protons of the amino group on carbon-carbon hydroxyl group and a methyl group. This confirms the cis arrangement of two functional groups (trans location, which is devoid of the spatial proximity would not show such effect), which in turn confirms that this isomer is (1S, 3R) -3- (dibenzylamino) -1-methylcyclohexanol.

I. (1S, 3R) -3-Amino-1-methylcyclohexanol. A solution of (1S, 3R) -3- (dibenzylamino) -1-methylcyclohexanol (5.0 g, 16.16 mmol) in ethanol (150 ml) was treated with palladium hydroxide on carbon and stirred under balloon filled with hydrogen gas overnight . After completion of the reaction as indicated by LCMS, the reaction mixture was filtered through a pad of celite and the filtrate concentrated to yield (1R, 3R) -3-amino-1-methylcyclohexanol (1.3 g, 62%) as a thick yellow oil.¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 2.87 (br. S., 1H), 1.64-1.74 (m, 1H), 1.47-1.59 (m, 2H), 1,21-1, 40 (m, 4H), 1,11-1,20 (m, 1H), 1.02 (s, 3H); MS (ESI) m / z 130,2 [M + 1]⁺.

J. 2 - ((1R, 4R) -4-Etoksitsiklogeksilamino) -4 - ((1R, 3S) -3-hydroxy-3-methylcyclohexylamine) -pyrimidine-5-carbonitrile. 4-Chloro-2 - ((1R, 4R) -4-etoksitsiklogeksilamino) -pyrimidine-5-carbonitrile (350 mg, 1.247 mmol), (1S, 3R) -3-amino-1-methylcyclohexanol (242 mg, 1.870 mmol) and DIEA (0.327 mL, 1.870 mmol) was dissolved in DMF (3.5 mL) in a screw cap vial. The reaction mixture was stirred at 70 ° C for 4 hours. After completion of reaction as indicated by LCMS and TLC, the reaction mixture was concentrated and the resulting solid was purified by chromatography on silica gel using a gradient of 0-100% ethyl acetate in hexane. Appropriate fractions were combined and concentrated to give 2 - ((1R, 4R) -4-etoksitsiklogeksilamino) -4 - ((1R, 3S) -3-hydroxy-3-methylcyclohexylamine) -pyrimidine-5-carbonitrile (0.356 g, 76% yield, 98,¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8,09-8,24 (m, 1H), 7,28-7,63 (m, 2H), 4,71-4,90 (m, 1H), 4.21 (d , J = 3,51 Hz, 1H), 3,57-3,78 (m, 1H), 3.43 (q, J = 7,03 Hz, 2H), 3,11-3,23 (m, 1H), 1,78-2,02 (m, 4H), 1,48-1,74 (m, 5H), 1,16-1,47 (m, 6H), 1,11-1,16 ( m, 4H), 1.08 (t, 3H); MS (ESI) m / z 374,5 [M + 1]⁺.

Example 21: 2 - ((1R, 4R) -4-Etoksitsiklogeksilamino) -4 - ((1R, 3S) -3-hydroxycyclohexylamino) pyrimidine-5-carbonitrile

<img file="00000124.jpg" he="34" wi="66" img-format="tif" img-content="undefined" />

A. 2-Chloro-4 - ((1R, 3S) -3-gidroksitsiklogeksilamino) pyrimidine-5-carbonitrile and 4-chloro-2 - ((1R, 3S) -3-gidroksitsiklogeksilamino) pyrimidine-5-carbonitrile. 2,4-dichloropyrimidine-5-carbonitrile (900 mg, 5.17 mmoly) in bezvodnom эtanole (5 mL) and (1R, 3S) -3-aminotsiklogeksanol (624 mg, 5.43 mmoly; prepared how described in Tetrahedron: Asymmetry 15 (2004) 2051-2056) in bezvodnom эtanole (5 ml) peremeshivali at -60 ° C and kaplyam dobavlyali zatem DIЭA (1.0 g, 7.75 mmoly). Smesy peremeshivali at -60 ° C for 1 h and at zatem komnatnoy temperature nochi. Letuchie fractions manure removal, and tverdыy ostatok ochishtali on silica gel (эlyuiruya 9.1% -33% эtilatsetatom in petroleynom эfire) with polucheniem 4-chloro-2 - ((1R, 3S) -3-gidroksitsiklogeksilamino) pyrimidine-5-carbonitrile (600 mg, 2.38 mmoly, vыhod 46%) in he saw belogo tverdogo substances and 2-chloro-4 - ((1R,¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8.55 (s, 1H), 8.46 (d, J = 7,81 Hz, 1H), 4.83 (d, J = 3,90 Hz, 1H), 3.95 -4.11 (m, 1H), 3.45-3.61 (m, 1H), 1.93 (d, J = 11,71 Hz, 1H), 1.60-1.84 (m, 3H ), 1,03-1,50 (m, 4H); MS (ESI) m / z 253,2 [M + 1]⁺) As a white solid. Minor regioisomer regiochemistry was confirmed in Step B below.

B. (1S, 3R) -3- (5- (Aminomethyl) pyrimidin-4-ylamino) cyclohexanol. To a mixture of 2-chloro-4 - ((1R, 3S) -3-hydroxycyclohexylamino) pyrimidine-5-carbonitrile (70 mg, 0.277 mmol) and ammonium hydroxide (500 uL, 12.84 mmol) in ethanol (4 mL) was added Raney nickel (16.26 mg, 0.277 mmol). The resulting mixture was discharged and then stirred under balloon pressure and ambient temperature of the ambient atmosphere of hydrogen overnight. Ethanol was removed in vacuo and the residual solid was purified using a preparative reversed phase HPLC (5-80% acetonitrile + 0.1% TFA in water + 0.1% TFA, over 30 min). Fractions containing product were concentrated under reduced pressure. The resulting solid was again dissolved in methanol (5 ml) was passed through a SPE tube with a Varian Stratospheres HCO3 polymer to remove TFA (0.9 mmol bicarbonate equiv.), and then concentrated under reduced pressure to obtain the compound of the title as an oil, which was used for NMR purposes only. Regiochemistry was confirmed by the presence of two distinct peaks in the spectrum of aromatic¹H-NMR and NOE observation signal between C5 hydrogen chloride and only one of these aromatic peaks in the NOESY spectrum. ¹H-ЯМР (400 МГц, DMCO-d₆) Δ hr. / Million 8.32 (s, 1H), 7.92 (s, 1H), 7.32 (d, J = 7.48 Hz, 1H), 4.67 (d, J = 3, 87 Hz, 1H), 3,88-4,01 (m, 1H), 3.59 (s, 2H), 3.49 (d, J = 3,61 Hz, 1H), 2,06-2, 16 (m, 1H), 1.99 (br. s., 2H), 1.81 (t, J = 13,28 Hz, 2H), 1.69 (dt, J = 13.35, 3.51 Hz, 1H), 1,01-1,35 (m, 4H). MS (ESI) m / z 223,5 [M + 1]⁺.

C. 2 - ((1R, 4R) -4-Etoksitsiklogeksilamino) -4 - ((1R, 3S) -3-hydroxycyclohexylamino) pyrimidine-5-carbonitrile. A mixture of 2-chloro-4 - ((1R, 3S) -3-hydroxycyclohexylamino) pyrimidine-5-carbonitrile (270 mg, 1.07 mmol), (1R, 4R) -4-etoksitsiklogeksanamina (289 mg, 1.60 mmol; synthesis described herein) and cesium carbonate (698 mg, 2.14 mmol) in anhydrous n-butanol (10 ml) was stirred at 80 ° C for 1 day and then at 120 ° C for 5 hours The mixture was. extracted between water and DCM. The organic layer was combined, concentrated and purified on silica gel (eluting with 9.1% -33% ethyl acetate in petroleum ether) to give 2 - ((1R, 4R) -4-etoksitsiklogeksilamino) -4 - ((1R, 3S) -3- hydroxycyclohexylamino) pyrimidine-5-carbonitrile (202 mg, 0.56 mmol, yield 52%) as a white powder.¹H-NMR (400 MHz, DMSO-d₆): Δ h / million 8.11 (s, 1H), 7.10 (s, 1H), 6.95 (s, 1H), 4.51 (d, J = 3,6, 1H), 4. 05 (s, 1H), 3,67 (c, 1H), 3,58-3,55 (m, 1H), 3,47 (q, J = 6,8, 2H), 3,24-3 19 (m, 1H), 2,00-1,90 (m, 5H), 1,73 (s, 3H), 1,47-1,25 (m, 8H), 1.10 (t, J = 7.2, 3H); MC (ESI): m / z 359,9 [M + 1]⁺.

Example 22: 2- (Tsiklogeksilamino) -4 - ((1R, 3S) -3-gidroksitsiklogeksilamino) pyrimidine-5-carbonitrile

<img file="00000125.jpg" he="32" wi="50" img-format="tif" img-content="undefined" />

A. 2- (Ciklogeksilamino) -4 - ((1R, 3S) -3-gidroksiciklogeksilamino) pyrimidine-5-carbonitrile. Ciklogeksanamina solution (0.181 ml, 1.583 mmol) in DMSO (5 ml), 2-chloro-4 - ((1R, 3S) -3-gidroksiciklogeksilamino) pyrimidine-5-carbonitrile (0.200 g, 0.791 mmol; synthesis are disclosed in the Present Description ), and DIEA (0.276 ml, 1.583 mmol) at 70 ° nagrevali S within a night. After the completion of reactions, to what pointing ZH-MS and TSH, reakcionnuû blend ostavlâli ohlaždatʹsâ to komnatnoj temperature and koncentrirovali. Received Syro substance Cleansing via chromatography on silica gel, using a gradient of 0% -70% ethyl acetate (containing 10% methanol, Solid Ammonia) in Hexane. Product fractions celevogo obʺedinâli and koncentrirovali with access 2- (ciklogeksilamino) -4 - ((1R, 3S) -3-gidroksiciklogeksilamino) pyrimidine-5-carbonitrile (0.220 g, 88% output, 98,¹H-NMR (400 MHz, DMSO-d₆) Δ 8,08-8,21 (m, 1H), 7,08-7,56 (m, 2H), 4.74 (d, J = 3,90 Hz, 1H), 3,93-4, 13 (m, 1H), 3,44-3,77 (m, 2H), 1.83-2.02 (m, 2H), 1.65-1.82 (m, 6H), 1.58 ( d, J = 14,84 Hz, 1H), 1.32-1.45 (m, 2H), 1,08-1,30 (m, 7H); MS (ESI) m / z 316,4 [M + 1]⁺.

Example 23: 4 - ((1R, 3S) -3-Gidroksitsiklogeptilamino) -2 - ((1R, 4R) -4- (2,2,2-triftorэtoksi) tsiklogeksilamino) pyrimidine-5-carbonitrile

<img file="00000126.jpg" he="33" wi="69" img-format="tif" img-content="undefined" />

A. 4 - ((1R, 3S) -3-Gidroksitsiklogeptilamino) -2- (methylthio) pyrimidine-5-carbonitrile. To a stirred solution of 4-chloro-2- (methylthio) pyrimidine-5-carbonitrile (0.4 g, 2.155 mmol) and hydrochloride (1S, 3R) -3-aminotsiklogeptanola (0.428 g, 2.59 mmol; synthesis described in the present description) in DMF (3 mL) was added DIEA (1.126 mL, 6.46 mmol) and stirred at 60 ° C for 1 hour.

LCMS showed complete reaction. The reaction mixture was cooled to room temperature and poured into water (50 ml). The suspension was stirred for five minutes, then filtered to give 4 - ((1R, 3S) -3-gidroksitsiklogeptilamino) -2- (methylthio) pyrimidine-5-carbonitrile (0.404 g, 1.451 mmol, 67.4% yield) as a off white solid;¹Н-ЯМР (ie ДМСО₆, 400 MHz):. Δ h / million 8.39 (s, 1H), 8.00 (d, J = 7,4 Hz, 1H), 4.63 (d, J = 3,9 Hz, 1H) 4.21 (br. s., 1H), 3.74 (td, J = 8.5, 4.1 Hz, 1H), 2.47 (s, 3H), 1,66-1,97 ( m, 5H), 1,35-1,66 h / million (m, 5H).; MS (ESI) m / z 138,1 [M + 1]⁺.

B. 4 - ((1R, 3S) -3-Gidroksitsiklogeptilamino) -2 - ((1R, 4R) -4- (2,2,2-trifluoroethoxy) cyclohexylamino) pyrimidine-5-carbonitrile. 4 - ((1R, 3S) -3-Gidroksitsiklogeptilamino) -2- (methylthio) pyrimidine-5-carbonitrile (381 mg, 1, 369 mmol) was dissolved in NMP (7 mL). in portions was then added mCPBA (675 mg, 3.01 mmol) at 0 ° C, and the reaction mixture was stirred at room temperature for 90 min. The reaction mixture was added (1R, 4R) -4- (2,2,2-trifluoroethoxy) cyclohexanamine (0.405 g, 2.054 mmol) (prepared as described herein) and DIEA (0.956 mL, 5.48 mmol) and stirred for 5 minutes at room temperature. The reaction mixture was further stirred at 80 ° C for 30 min after which LCMS showed complete reaction mixture. The reaction mixture was cooled to room temperature and diluted with water (30 mL). The mixture was allowed to stir at room temperature for 4 hours, during which time the desired product precipitated. The product was filtered and the collected solid washed with water and then hexanes and dried in vacuo to give 4 - ((1R, 3S) -3-gidroksitsiklogeptilamino) -2 - ((1R, 4R) -4- (2,2,2- trifluoroethoxy) -tsiklogeksilamino) -pyrimidine-5-carbonitrile (0.444 g, 1.039 mmol, 76% yield) as a brown solid;¹Н-ЯМР (ie ДМСО₆, 400 MHz):. Δ h / million 8,08-8,22 (m, 1H), 7,06-7,59 (m, 2H), 4.51-4.60 (m, 1H), 4 , 01-4,24 (m, 1H), 3,54-3,78 (m, 2H), 3.44 (q, J = 7,0 Hz, 2H), 3.11-3.24 (m ., 1H), 1.88-2.05 (m, 4H), 1,12-1,88 (m, 14H), 1.08 parts / million (t, J = 7,0 Hz, 3H); MS (ESI) m / z 374,2 [M + 1]⁺.

Example 24: 4 - ((1R, 3S) -3-Gidroksitsiklogeptilamino) -2 - ((1R, 4R) -4-hydroxycyclohexylamino) pyrimidine-5-carbonitrile

<img file="00000127.jpg" he="32" wi="58" img-format="tif" img-content="undefined" />

A. 4 - ((1R, 3S) -3-Gidroksiciklogeptilamino) -2- (methylsulfonyl) pyrimidine-5-carbonitrile. 4 - ((1R, 3S) -3-Gidroksiciklogeptilamino) -2- (methylthio) pyrimidine-5-carbonitrile (457 mg, 1.642 mmol; synthesis are disclosed in the Present Description) rastvorâli in NMP (10 ml). Thereafter Porcia dobavlâli mCPBA (736 mg, 3.28 mmol) at 0 ° C, and blend reakcionnuû peremešivali in week 2 h at komnatnoj temperature. ZH-MS indicated the expense source substances and the Education sulʹfonovogo promežutočnogo product. This reakcionnuû mix perenosili the Stadio FOLLOWING no extra cleaning. MS (ESI) m / z 311.1 [M + 1]⁺.

B. 4 - ((1R, 3S) -3-Gidroksitsiklogeptilamino) -2 - ((1R, 4R) -4-hydroxycyclohexylamino) pyrimidine-5-carbonitrile. To the reaction mixture from the previous step was added (1R, 4R) -4-aminocyclohexanol hydrochloride (0.374 g, 2.465 mmol) and DIEA (1.435 mL, 8.22 mmol). The reaction mixture was stirred at 80 ° C for 1 hour, and then the reaction mixture was cooled at room temperature. The solvent was evaporated under reduced pressure, and the resulting solid was purified by flash chromatography (0-10% methanol saturated with ammonia in DCM) to give 4 - ((1R, 3S) -3-gidroksitsiklogeptilamino) -2 - ((1R, 4R) -4-hydroxycyclohexylamino) pyrimidine-5-carbonitrile (0.250 g, 0.724 mmol, 44.0% yield) as a brown solid.¹H-NMR (400 MHz, DMSO-d₆) Δ 8,07-8,21 (m, 1H), 7,05-7,55 (m, 2H), 4,52-4,59 (m, 2H), 4,02-4,25 (m , 1H), 3,51-3,79 (m, 2H), 3,35-3,42 (m, 1H), 1,75-1,97 (m, 8N) 1,39-1,70 (m, 6H), 1,14-1,31 (m, 4H); MS (ESI) m / z 346,1 [M + 1]⁺.

Example 25: 2- (4-Gidroksibitsiklo [2.2.2] octane-1-ylamino) -4- (isopropylamino) pyrimidine-5-carboxamide

<img file="00000128.jpg" he="28" wi="54" img-format="tif" img-content="undefined" />

A. dimethylcyclohexane-1,4-dicarboxylate. To a stirred solution of cyclohexane-1,4-dicarboxylic acid (100 g, 0.58 mol) in anhydrous methanol (800 mL) was added sulfur dichloride (208 g, 1.75 mol) at 0 ° C. The reaction mixture was stirred at room temperature overnight. The solution was then concentrated and the solid residue was poured into water. The mixture was extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and filtered. Concentration under reduced pressure gave dimethylcyclohexane-1,4-dicarboxylate (105 g, 0.53 mol, 90.5% yield) which was used in the next step without further purification.

B. Dimethyl-1- (2-chloroethyl) -cyclohexane-1,4-dicarboxylate. To a solution of diisopropylamine (88 ml, 0.62 mol) in anhydrous THF (500 mL) was added n-butyllithium (240 mL, 0.6 mol, 2.5 M solution in hexane) over 20 minutes at -78 ° C. The mixture was stirred at 0 ° C under a nitrogen atmosphere for 30 min. To a mixture of dimethyl cyclohexane-1,4-dicarboxylate (100 g, 0.5 mol) and hexamethylphosphoramide (360 mL, 2 mol) in anhydrous THF (800 mL) was added lithium diisopropylamine (freshly prepared above) for 30 minutes at -40 ° C . After stirring for 1 hour at this temperature was added 1-bromo-2-chloroethane (42 mL, 0.5 mol) was added over 1 h. The mixture was stirred for 3 hours at -78 ° C, then warmed to room temperature and was stirred overnight. The reaction mixture was added an aqueous solution of hydrochloric acid (3N, 420 ml) and the mixture was stirred for 10 min. The solvent was removed by evaporation under reduced pressure. The aqueous layer was extracted with ethyl acetate (3 × 200 mL) and the combined extracts were washed with brine (2 × 300 ml) and dried over sodium sulfate. Concentration under reduced pressure gave dimethyl-1- (2-chloroethyl) -cyclohexane-1,4-dicarboxylate (116 g, 88% yield) which was used in the next step without further purification.¹Н-ЯМР (400 МГц, CDCl₃) Δ hr. / Million 3.72 (s, 3H), 3.65 (s, 3H), 3,46-3,42 (m, 2H), 2,33-2,21 (m, 3H), 2,05-1,85 (m, 4H), 1,58-1,42 (m, 2H), 1,25-1, 15 (m, 2H).

S. dimethylbicyclo [2.2.2] octane-1,4-dicarboxylate. To a solution of diisopropylamine (77 ml, 0.54 mol) in anhydrous THF (500 mL) was added n-butyllithium (210 mL, 0.53 mol, 2.5 M solution in hexanes) for 20 min at -78 ° C. The mixture was then stirred at 0 ° C under a nitrogen atmosphere for 30 min. To a mixture of dimethyl-1- (2-chloroethyl) -cyclohexane-1,4-dicarboxylate (116 g, 0.44 mol) and hexamethylphosphoramide (317 ml, 1.7 mol) in anhydrous THF (800 mL) was added lithium diisopropylamine (freshly prepared above) for 30 minutes at -40 ° C. The mixture was stirred for 2 hours at -78 ° C and then stirred overnight, leaving to warm at room temperature. The reaction mixture was added saturated aqueous ammonium chloride solution (200 ml) and the mixture was stirred for 10 min. The solvent was removed by evaporation under reduced pressure. The aqueous layer was extracted with ethyl acetate (3 × 200 mL). The combined extracts were washed with brine (2 × 300 ml) and dried over sodium sulfate. Concentration under reduced pressure gave a crude product which was purified by chromatography on a silica gel column (10% ethyl acetate in petroleum ether) to give the compound of the title (58 g, 0.25 mol, 50% yield in two steps).¹Н-ЯМР (400 МГц, CDCl₃) Δ hr. / Million 3.65 (s, 6H), 1.81 (s, 12H).

D. 4- (Methoxycarbonyl) bicyclo [2.2.2] octane-1-carboxylic acid. A solution dimethylbicyclo [2.2.2] octane-1,4-dicarboxylate (58.0 g, 0.25 mol) in methanol (600 ml) was heated at reflux. To this solution was added a solution of potassium hydroxide (9.8 g, 0.175 mol) in methanol (100 ml) and water (12 ml) for 30 minutes. The reaction mixture was refluxed for 24 hours. The solvent was then removed, and the solid residue was diluted with water. The aqueous solution was extracted with ethyl acetate (2x200 mL) to recover the starting material (22.0 g), and the aqueous layer was acidified to pH 3 by adding hydrochloric acid. A precipitate formed and it was extracted with ethyl acetate (3 × 300 mL). The combined extracts were washed with saturated brine, dried over sodium sulfate and concentrated to give the product,¹Н-ЯМР (400 МГц, CDCl₃) δ ч./млн 3,65 (с, 3Н), 1,81 (s. 12Н); МС (ESI) m/z 211,3 [М-Н]^-.

E. Methyl 4-bromobicyclo [2.2.2] octane-1-carboxylate. To a suspension of 4- (methoxycarbonyl) bicyclo [2.2.2] octane-1-carboxylic acid (11.0 g, 51.8 mmol) in acetone (80 ml) was added 1M aqueous sodium hydroxide solution (51.8 ml, 51, 8 mmol). Then added a solution of silver nitrate (8.8 g, 51.9 mol) in water (10 ml). The resulting precipitate was collected by filtration, washed with water, acetone and diethyl ether and dried in vacuo at 115 ° C for 4 hours. The resulting (4- (methoxycarbonyl) bicyclo [2.2.2] octan-1-carbonyloxy) Silver (15, 3 g, 47.9 mmol) was suspended in hexane (125 ml), then the reaction mixture is added bromine (7.7 g, 48.1 mmol) for 30 minutes at room temperature. After complete addition, the reaction mixture was stirred at room temperature for another 30 minutes. The reaction mixture was filtered to remove solid, and the filter cake washed with hexane (4 × 150 mL). The combined organic filtrates were washed with saturated sodium bicarbonate (2 × 150 mL) and brine (200 ml) and then dried over magnesium sulfate. Concentration in vacuo gave a crude product which was purified by chromatography on a silica gel column (5% ethyl acetate in petroleum ether) to give the compound of the title (4.2 g, 0.17 mol, 33% yield in two steps) .¹Н-ЯМР (400 МГц, CDCl₃) D ч. / Млн 3,64 (с, 3Н), 2,27-2,20 (м, 6Н), 1,98-1, 94 (м, 6Н).

F. 4-hydroxybicyclo [2.2.2] octane-1-carboxylic acid. Methyl 4-bromobicyclo [2.2.2] octane-1-carboxylate (17.0 g, 69.0 mol) was refluxed in aqueous sodium hydroxide (1500 mL, 1%) for 24 hours. After cooling the reaction solution was acidified with hydrochloric acid (6N, 100 mL) and extracted with diethylether (6 × 500ml). The combined ether layers were dried over magnesium sulfate and concentrated to give compound the title compound (10.4 g, 61.1 mmol, 89% yield), which was used in the next step without further purification. MS (ESI) m / z 169,2 [M-H]^-.

G. Benzyl 4-hydroxybicyclo [2.2.2] octan-1-ylcarbamate. To a solution of 4-hydroxybicyclo [2.2.2] octane-1-carboxylic acid (10.4 g, 61.1 mmol) in dioxane (150 mL) was added DIEA (11.8 g, 91.5 mmol), diphenylphosphoryl azide (25 g, 91.5 mmol) and benzyl alcohol (131 g, 1.22 mol). The mixture was stirred at 80 ° C overnight. The reaction mixture was concentrated under reduced pressure to remove dioxane, and benzyl alcohol (100 ° C, 2 mm Hg. V.). The solid residue was purified by chromatography on a silica gel column (5% methanol in DCM) to give the product of the title (15.4 g, 54 mmol, 91% yield).¹Н-ЯМР (400 МГц, CDCl₃) Δ hr. / Million 7.35-7.30 (m, 5H), 5.03 (s, 2H), 4.55 (br. S., 1H), 2,01-1,95 (m, 6H), 1.77-1.72 (m, 6H); MS (ESI) m / z 276,3 [M + H]⁺.

H. hydrochloride 4-aminobicyclo [2.2.2] octan-1-ol. To a solution of benzyl 4-hydroxybicyclo [2.2.2] octan-1-ylcarbamate (14.8 g, 53 mmol) in methanol (200 mL) was added palladium on carbon (0.5 g, 10%). The reaction mixture was stirred at 50 ° C in a hydrogen atmosphere (50 psig. Inch) overnight and filtered through celite. The filtrate was concentrated and the solid residue was added to hydrochloric acid in methanol (10%, 50 mL). The mixture was stirred for 2 hours at room temperature. Then the mixture was concentrated again and added with THF (20 mL). The mixture was stirred at room temperature for 1 h, and the residue was collected and dried to give the product of the title (6.7 g, 36 mmol, 70% yield).¹H-ЯМР (ДМСО-d₆) Δ 8,00 (s, 3H), 4.48 (br. S, 1H), 1,76-1,80 (m, 6H), 1,58-1,61 (m, 6H). MS (ESI) m / z 142,1 [M + 1]⁺.

I. Эtil-4- (isopropylamino) -2- (methylthio) pyrimidine-5-carboxylate. Smesy эtil-4-chloro-2- (methylthio) pyrimidine-5-carboxylate (10 g, 43.0 mmoly) propan-2-amine (4.21 mL, 49.4 mmoly) and DIЭA (9.76 ml , 55.9 mmoly) in эtanole (140 ml) was heated at 60 ° C for nochi. Then cooled in air temperature komnatnoy rastvoritely kontsentrirovali in ponizhennom davlenii and dobavlyali vodu. Vodnuyu fazu эkstragirovali three rasa эtilatsetatom and obaedinennыe organicheskie fazы dried over sulyfatom Magna, filytrovali and uparivali with polucheniem эtil-4- (isopropylamino) -2- (methylthio) pyrimidine-5-carboxylate (10.10 g, 39.5 mmoly, 92% vыhod) in Vide bestsvetnogo oils. MS (ESI) m / z 256,1 [M + 1]⁺.

J. 4- (Isopropylamino) -2- (methylthio) pyrimidine-5-carboxylic acid. In a round bottom flask was dissolved ethyl 4- (isopropylamino) -2- (methylthio) pyrimidine-5-carboxylate (10.97 g, 43.0 mmol) in ethanol (150 ml) and then aqueous sodium hydroxide solution (1 M , 129 mL, 129 mmol). The resulting mixture was stirred overnight at room temperature and then the solvent was evaporated under reduced pressure. Was slowly added an aqueous solution of citric acid (2M, 129 mL, 258 mmol) and the resulting mixture was stirred for 0.5 hours at room temperature. The suspension was filtered and the solids washed twice with water (2 × 50 mL) and then dried in a vacuum oven at 45 ° C overnight to give 4- (isopropylamino) -2- (methylthio) pyrimidine-5-carboxylic acid (8 38 g, 36.9 mmol, 86% yield); MS (ESI) m / z 228,4 [M + 1]⁺.

K. 4- (isopropylamino) -2- (methylthio) pyrimidine-5-carboxamide. 4- (Isopropylamino) -2- (methylthio) pyrimidine-5-karbonovuû acid (8.38 g, 36.9 mmol), and HATU (21.03 g, 55.3 mmol) in 250 ml of obʺedinâli kruglodonnoj chicken legs, and subsequently dobavlâli DMF (92 ml). After that dobavlâli ammonium hydrochloride (9.86 g, 184 mmol) and DIEA (32 ml, 184 mmol), and the mixture peremešivali komnatnoj at a temperature in within a night. Be dissolved in koncentrirovali ponižennom dobavlâli pressure and water (150 ml). Polučennuû suspension filʹtrovali, promyvali water and dried in high vacuum overnight in a week with receipt of 4- (isopropylamino) -2- (methylthio) pyrimidine-5-carboxamide (8 g, 35.4 mmol, 96% output); MS (ESI) m / z 227.4 [M + 1]⁺.

L. 4- (isopropylamino) -2- (methylsulfinyl) pyrimidine-5-carboxamide and 4- (isopropylamino) -2- (methylsulfonyl) pyrimidine-5-carboxamide. To a solution of 4- (isopropylamino) -2- (methylthio) pyrimidine-5-carboxamide (641 mg, 2.8 mmol) in NMP (6 ml) dobavlâli mCPBA (852 mg, 4.2 mmol, 85% purity) at 0 ° S. Reakcionnuû mix peremešivali in week 1 h at komnatnoj temperature. Thereafter dobavlâli water (25 ml), in which rastvorâli suspension within a short time with receipt of promežutka only More žirnogo of one residue, which otfilʹtrovyvali. Recieved filtrate koncentrirovali in ponižennom pressure with receipt of the mixture, the specified in the header, in NMP, þ ispolʹzovali in next Stages at no extra cleaning. MS (ESI) m / z 243.3, 259.2 [M + 1]⁺.

M. 2- (4-Gidroksibiciklo [2.2.2] octane-1-ylamino) -4- (isopropylamino) pyrimidine-5-carboxamide. To a solution of 4- (isopropylamino) -2- (methylsulfinyl) pyrimidine-5-carboxamide and 4- (isopropylamino) -2- (methylsulfonyl) pyrimidine-5-carboxamide in NMP (from the previous stadii, 2.8 mmol) dobavlâli hydrochloride 4 -aminobicyclo [2.2.2] octan-1-ol (500 mg, 2.8 mmol), DIEA (1.1 g, 8.4 mmol) and nagrevali at a temperature of 100 ° C in 3 days a week. Polučennuû blend koncentrirovali ponižennom in pressure, and the tire tverdyi Cleansing via preparative tonkoslojnoj Chromatography with receipt of the final product (74.1 mg, 8.2% output).¹H-ЯМР (ДМСО-d₆) Δ hr. / Million 8.88 (br. S, 1H), 8.31 (s, 1H), 7,5-6,5 (br. S, 2H), 5.76 (s, 1H) 4.25 (s, 1H), 4.11 (br. s, 1H), 2,05-1,97 (m, 6H), 1,61-1,54 (m, 6H), 1,24- 1.12 (m, 6H); MS (ESI) m / z 320,2 [M + H]⁺; Purity = 96.5% at 214 nm, Purity = 97.7% at 254 nm.

Example 26: 4- (tert-butylamino) -2 - ((1R, 4R) -4-gidroksiciklogeksilamino) pyrimidine-5-carboxamide

<img file="00000129.jpg" he="28" wi="53" img-format="tif" img-content="undefined" />

A. Ethyl 4- (tert-butylamino) -2- (methylthio) pyrimidine-5-carboxylate. A mixture of ethyl 4-chloro-2- (methylthio) pyrimidine-5-carboxylate (3 g, 12.89 mmol), 2-methylpropan-2-amine (1.565 mL, 14.83 mmol) and DIEA (2.93 ml , 16.76 mmol) in ethanol (20 ml) was heated at 60 ° C overnight. After cooling at room temperature, the solvent was concentrated under reduced pressure, and water was added. The aqueous phase was extracted three times with ethyl acetate and the combined organic phases were dried over anhydrous magnesium sulfate, filtered and evaporated to give ethyl 4- (tert-butylamino) -2- (methylthio) pyrimidine-5-carboxylate (3.20 g, 11 86 mmol, 92% yield) as a colorless oil. MS (ESI) m / z 269,5 [M + 1]⁺.

B. 4- (tert-butylamino) -2- (methylthio) pyrimidine-5-carboxylic acid. In a round bottom flask in ethanol (40 ml) was dissolved ethyl 4- (tert-butylamino) -2- (methylthio) pyrimidine-5-carboxylate (3.2 g, 11.88 mmol) and then 1 M aqueous hydroxide solution sodium (35.6 mL, 35.6 mmol). The resulting mixture was stirred overnight at room temperature and then the solvent was evaporated under reduced pressure. After slowly added 2M aqueous citric acid solution (35.6 mL, 71.3 mmol) and the resulting mixture was stirred for 0.5 hours at room temperature. The suspension was filtered and the solids washed twice with water (2 × 50 mL) and then dried in a vacuum oven at 45 ° C overnight to yield 4- (tert-butylamino) -2- (methylthio) pyrimidine-5-carboxylic acid (2.83 g, 11.73 mmol, 99% yield). MS (ESI) m / z 242,3 [M + 1]⁺.

C. 4- (tert-butylamino) -2- (methylthio) pyrimidine-5-carboxamide. 4- (tert-butylamino) -2- (methylthio) pyrimidine-5-karbonovuю kislotu (2.83 g, 11.73 mmolь) and geksaftor-phosphate (V) 2- (3H- [1,2,3] triazolo [4,5-b] pyridin-3-yl) -1,1,3,3-tetrametilizouroniя (6.69 g, 17.59 mmolь) obъedinяli kruglodonnoй in 250 ml flasks and zatem dobavlяli DMF (29 ml). After chego dobavlяli gidrohlorid AMMO (3.14 g, 58.6 mmolь) and DIЭA (10.21 mL, 58.6 mmolь) and smesь peremeshivali in komnatnoй temperature nochi. Rastvoritelь koncentrirovali in ponizhennom davlenii and dobavlяli vodu (150 ml). Poluchennuю suspenziю filьtrovali, promыvali water and dried in vacuum over vыsokom nochi polucheniem with 4- (tert-butylamino) -2- (methylthio) pyrimidine-5-carboxamide (2.54 g, 10.57 mmolь, vыhod 90%). MS (ESI) m / z 241,2 [M + 1]⁺.

D. 4- (tert-butylamino) -2- (metilsulьfonil) pyrimidine-5-carboxamide. K peremeshivaemomu solvent 4- (tert-butylamino) -2- (methylthio) pyrimidine-5-carboxamide (0.6 g, 2.497 mmolь) in NMP (5 ml) dobavlяli mCPBA (0,839 g, 3.74 mmolь) at 0 ° c peremeshivanie prodolzhali in komnatnoй temperature for 1 h. CHO-MS showed the complete transformation in celevoй product. Reakcionnuю smesь ispolьzovali in sleduющeй dopolnitelьnoй reactions without purification. MS (ESI) m / z 273,2 [M + 1]⁺.

E. 4- (tert-butylamino) -2 - ((1R, 4R) -4-gidroksiciklogeksilamino) pyrimidine-5-carboxamide. K solvent 4- (tert-butylamino) -2- (metilsulьfonil) pyrimidine-5-carboxamide from predыduщeй stages dobavlяli DIЭA (2.181 mL, 12.49 mmolь) and gidrohlorid (1R, 4R) -4-aminociklogeksanola (0.568 g, 3 75 mmolь) and reakcionnuю smesь peremeshivali at 90 ° C for 16 h. Rastvoritelь uparivali in ponizhennom davlenii and poluchennoe tverdoe ochiщali substance, ispolьzuя preparativnuю VЭZHH convertibility with a phase (0-50% acetonitrile + 0.1% TFU in water + 0.1% TFU, over 30 min). Fractions soderzhaщie product koncentrirovali in ponizhennom davlenii. Poluchennoe tverdoe eщe different rastvorяli substance in methanol (5 ml) permeable cherez trubku SPE with polimerom Varian Stratospheres NSO3 dlya succeeded TFU (0.9 mmolь bicarbonate эkviv.)¹H-ЯМР (ДМСО-d₆, 400 MHz) δ hr. / Million 0,82-0,88 (m, 1H) 1.14-1.30 (m, 5H), 1.42 (s, 9H), 1.85 (d, J = 4 , 30 Hz, 4H) 3.38 (br. s, 1H) 3.59 (d, J = 7,42 Hz, 1H) 4.54 (s, 1H) 7.02 (d, J = 7,81 Hz, 1H), 8.32 (s, 1H), 9.18 (s, 1H); MC (ESI): m / z 308,1 [M + 1]⁺.

Example 27: 4 - ((1R, 3R, 4R) -3-Gidroksi-4-metiltsiklogeksilamino) -2- (isopropylamino) pyrimidine-5-carboxamide

<img file="00000130.jpg" he="42" wi="47" img-format="tif" img-content="undefined" />

A. 4 - ((1R, 3R, 4R ) -3- Hydroxy-4-methylcyclohexylamine) -2- (methylthio) pyrimidine-5-carbonitrile. To a stirred solution of 4-chloro-2- (methylthio) pyrimidine-5-carbonitrile (310 mg, 1.670 mmol) and hydrochloride of (1R, 2R, 5R) -5 - amino-2-methylcyclohexanol (304 mg, 1.837 mmol; synthesis described herein) in DMF (2.4 mL), Dob vlyali DIEA (0.873 mL, 5.01 mmol). The resulting mixture was stirred at 60 ° C for 2 hr. LCMS showed the reaction was complete. The solvent was evaporated under reduced pressure and the solid residue was diluted with 150 ml ethyl acetate and 50 ml of water. The layers were separated, and the aqueous phase was extracted with 75 ml of ethyl acetate. The combined ethyl acetate layers were washed with brine (2 × 50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to an oil which solidified on standing to give 4 - ((1R, 3R, 4R) -3-hydroxy-4-methylcyclohexylamine) -2- (methylthio) pyrimidine-5-carbonitrile (418 mg, 1.503 mmol, 90% yield). MS (ESI) m / z 279,3 [M + 1]⁺.

B. 4 - ((1R, 3R, 4R) -3-Gidroksi-4-metiltsiklogeksilamino) -2- (metilsulyfonil) pyrimidine-5-carbonitrile. K rastvoru 4 - ((1R, 3R, 4R) -3-gidroksi-4-metiltsiklogeksilamino) -2- (methylthio) pyrimidine-5-carbonitrile (400 mg, 1.437 mmoly) in NMP (5 ml) dobavlyali mCPBA (805 mg , 3.59 mmoly) at 0 ° C, and reaktsionnuyu smesy peremeshivali over 3 hours at komnatnoy temperature. Poluchennыy simply entails adjacent ispolyzovali in sleduyushtey dopolnitelynoy stages without purification. MS (ESI) m / z 311,4 [M + 1]⁺.

C. 4 - ((1R, 3R, 4R) -3-Gidroksi-4-metiltsiklogeksilamino) -2- (isopropylamino) pyrimidine-5-carbonitrile. K rastvoru 4 - ((1R, 3R, 4R) -3-gidroksi-4-metiltsiklogeksilamino) -2- (metilsulyfonil) pyrimidine-5-carbonitrile (446 mg, 1.437 mmoly) around predыdushtey stages dobavlyali propan-2-amine (0.367 ml, 4.31 mmoly) and DIЭA (1.004 mL, 5.75 mmoly). Reaktsionnuyu smesy peremeshivali at 80 ° C for 4 h and zatem ostavlyali ohlazhdatysya to temperaturы okruzhayushtey sredы. Rastvoritely uparivali at ponizhennom davlenii and tverdыy ostatok ochishtali with pomoshtyyu chromatographies on silica gel (0-90% эtilatsetat in Gexto) with polucheniem 4 - ((1R, 3R, 4R) -3-gidroksi-4-metiltsiklogeksilamino) -2- (isopropylamino ) pyrimidine-5-carbonitrile (381 mg, 1,317 mmoly, 92% vыhod). MS (ESI) m / z 290,2 [M + 1]⁺.

D. 4 - ((1R, 3R, 4R) -3-Gidroksi-4-metiltsiklogeksilamino) -2- (isopropylamino) pyrimidine-5-carboxamide. 4 - ((1R, 3R, 4R) -3-Gidroksi-4-metiltsiklogeksilamino) -2- (isopropylamino) pyrimidine-5-carbonitrile (0.38 g, 1,313 mmoly) rastvoryali in DMSO (5 mL). K эtomu rastvoru dobavlyali 50% vodnыy simply entails gidroksida sodium (0.103 ml, 1,970 mmoly) and 30% vodnыy simply entails perekisni hydrogen (0.101 mL, 0.985 mmoly) at komnatnoy temperature. Zatem reaktsionnuyu smesy peremeshivali at 50 ° C for 1 h. Then эtogo reaktsionnuyu smesy vыlivali in ledyanuyu vodu (15 ml), and poluchennuyu smesy peremeshivali over 1 h. Poluchennыy osadok filytrovali and promыvali water with polucheniem 4 - ((1R, 3R , 4R) -3-gidroksi-4-metiltsiklogeksilamino) -2- (isopropylamino) pyrimidine-5-carboxamide (0.210 g, 0.683 mmoly, 52% vыhod).¹H-ЯМР (ДМСО-d₆, 400 MHz) δ hr. / Million 0.94 (d, J = 6,40 Hz, 4H) 1.12 (d, J = 5,91 Hz, 9H) 1.65 (dd, J = 13,29 , 2.95 Hz, 1H) 1.92 (br. s., 1H) 2.15 (br. s., 1H) 2.97 (br. s., 1H), 3,81-4,14 ​​(m , 2H) 4.55 (d, J = 5,41 Hz, 1H), 6,70-7,02 (m, 1H) 8.34 (br. s., 1H) 8.92 (br. s., 1H); MS (ESI) m / z 308,0 [M + 1]⁺.

Example 28: 2- (bicyclo [1.1.1] pentane-1-ylamino) -4 - ((1R, 3R, 4R) -3-gidroksi-4-metiltsiklogeksilamino) pyrimidine-5-carboxamide

<img file="00000131.jpg" he="40" wi="48" img-format="tif" img-content="undefined" />

A. 2- (bicyclo [1.1.1] pentane-1-ylamino) -4 - ((1R, 3R, 4R) -3-gidroksi-4-metiltsiklogeksilamino) pyrimidine-5-carbonitrile. K rastvoru 4 - ((1R, 3R, 4R) -3-gidroksi-4-metiltsiklogeksilamino) -2- (metilsulyfonil) pyrimidine-5-carbonitrile (446 mg, 1.437 mmoly; synthesis described in the present activities as described) in NMP (5 ml ) dobavlyali gidrohlorid bicyclo [1.1.1] pentan-1-amine (258 mg, 2,155 mmoly; poluchennыy in sootvetstvii in Org. Lett., 13 (17): 4746-4748 (2011)) and DIЭA (1.255 mL, 7 18 mmoly). Reaktsionnuyu smesy peremeshivali at 80 ° C for 4 h and zatem ostavlyali ohlazhdatysya to temperaturы okruzhayushtey sredы. Rastvoritely uparivali at ponizhennom davlenii and tverdыy ostatok ochishtali flэsh-hromatografiey (0-90% эtilatsetat in Gexto) with polucheniem 2- (bicyclo [1.1.1] pentane-1-ylamino) -4 - ((1R, 3R, 4R) -3-gidroksi-4-metiltsiklogeksilamino) pyrimidine-5-carbonitrile (381 mg, 1.216 mmoly, 85% vыhod).⁺.

B. 2- (bicyclo [1.1.1] pentane-1-ylamino) -4 - ((1R, 3R, 4R) -3-gidroksi-4-metiltsiklogeksilamino) pyrimidine-5-carboxamide. 2- (bicyclo [1.1.1] pentane-1-ylamino) -4 - ((1R, 3R, 4R) -3-gidroksi-4-metiltsiklogeksilamino) pyrimidine-5-carbonitrile (0.38 g, 1.213 mmoly) rastvoryali in DMSO (26.9 mL) and эtot simply entails dobavlyali 50% vodnыy simply entails gidroksida sodium (0.097 mL, 1.213 mmoly) and 30% vodnыy simply entails perekisni hydrogen 0.137 mL, 1.213 mmoly) at komnatnoy temperature. Zatem reaktsionnuyu smesy peremeshivali at 50 ° C for 1 h. Reaktsionnuyu smesy cooled at komnatnoy temperature and ee vыlivali in 50 ml ledyanoy vodы. Belыy osadok sobirali of filytrovalynoy papers and dvazhdы promыvali water. Ostatok dried polucheniem 2- (bicyclo [1.1.1] pentane-1-ylamino) -4 - ((1R, 3R, 4R) -3-gidroksi-4-metiltsiklogeksilamino) pyrimidine-5-carboxamide (0.269 g, 0.812 mmoly , 67% vыhod).¹H-ЯМР (ДМСО-d₆, 400 MHz):. Δ h / million 0.94 (d, J = 6,25 Hz, 3H), 1,10-1,26 (m, 3H), 1.68 (d, J = 10,54 Hz, 1H) 1.92 (d, J = 10,93 Hz, 1H) 2.06 (s, 6H), 2.17 (d, J = 9,76 Hz, 1H) 2.46 (s, 1H) 2, 98 (br. s., 1H) 3.82-3.95 (m, 1H) 4.63 (br. s., 1H) 7.16 (br. s, 1H) 7.77 (br. s. ., 1H) 8.11 (br s, 1H), 8.33 (s, 1H), 9.24 (br s, 1H)...; MC (ESI): m / z 332,3 [M + 1]⁺.

Example 29: 4 - ((2-cycloprop-2-yl) amino) -2 - (((1 R, 4R) -4-gidroksiciklogeksil) amino) pyrimidine-5-carboxamide

<img file="00000132.jpg" he="32" wi="54" img-format="tif" img-content="undefined" />

A. 4 - ((2-cyclopropyl-2-yl) amino) -2- (methylthio) pyrimidine-5-carbonitrile. To a solution of 4-chloro-2- (methylthio) pyrimidine-5-carbonitrile (750 mg, 4.0 mmol) in DMF (8 mL) was added 2-cyclopropyl-2-amine (400 mg, 4.0 mmol) and DIEA (1560 mg, 12.0 mmol). The resulting mixture was stirred at 60 ° C for 2 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give a crude product which was purified by chromatography on a silica gel column (0-30% ethyl acetate in petroleum ether) to give compound the title compound (665 mg, 2.68 mmol, 66% yield) as a white solid substances. MS (ESI) m / z = 249,2 [M + H]⁺.

B. 4 - ((2-cycloprop-2-yl) amino) -2- (methylthio) pyrimidine-5-carboxamide. To a solution of peremešivaemomu 4 - ((2-cycloprop-2-yl) amino) -2- (methylthio) pyrimidine-5-carbonitrile (665 mg, 2.68 mmol) in DMSO (4 ml) solution Water dobavlâli perekisi Hydrogen (0.162 ml, 30%) and Water Sodium gidroksida solution (2.2 ml, 6 mol / l) solution. Polučennuû peremešivali mix at 50 ° C for 12 min, and then dobavlâli water. Filʹtrovali target product and dried under vacuum with receipt syrogo product (392 mg, 1.47 mmol, 55% output) in the form of a rigid white substances. MS (ESI) m / z 267.3 [M + N]⁺.

C. 4 - ((2-cycloprop-2-yl) amino) -2- (methylsulfinyl) pyrimidine-5-carboxamide and 4 - ((2-cycloprop-2-yl) amino) -2- (methylsulfonyl) pyrimidine 5-carboxamide. To ohlaždennomu (0 ° C) solution of 4 - ((2-cycloprop-2-yl) amino) -2- (methylthio) pyrimidine-5-carboxamide (390 mg, 1.46 mmol) in TGF (6 ml) Porcia dobavlâli mPBA (447 mg, 2.2 mmol). Reakcionnuû mix peremešivali the week 0.5 h at 0 ° C. Mixture koncentrirovali in vacuo and the Cleansing via chromatography on a silica gel column with (2.5% -10% methanol in DCM) with receipt of a mixture of 4 - ((2-cycloprop-2-yl) amino) -2- (methylsulfinyl) pyrimidine 5-carboxamide and 4 - ((2-cycloprop-2-yl) amino) -2- (methylsulfonyl) pyrimidine-5-carboxamide (382 mg, 1.32 mmol, 90% output). MS (ESI) m / z 299.1 [M + N]⁺ and 283.1 [M + H]⁺.

D. 4 - ((2-cycloprop-2-yl) amino) -2 - (((1 R, 4R) -4-gidroksiciklogeksil) amino) pyrimidine-5-carboxamide. A mixture of 4 - ((2-cycloprop-2-yl) amino) -2- (methylsulfinyl) pyrimidine-5-carboxamide, 4 - ((2-cycloprop-2-yl) amino) -2- (methylsulfonyl) pyrimidine-5 carboxamide (191 mg, 0.66 mmol), (1R, 4R) -4-aminociklogeksanola (114 mg, 0.99 mmol), DIEA (256 g, 1.98 mmol) and NMP (5 mL) and obʺedinâli nagrevali at a temperature of 100 ° C in the night a week. Polučennuû koncentrirovali mix, and residual tverdyi Cleansing HPLC (5-95% acetonitrile in water) with receipt of Connection, specified in the header (129.5 mg, 0.39 mmol, 59% output).¹H-ЯМР (400 МГц, CDCl₃): Δ h / million 8.96 (s, 1H), 8.09 (s, 1H), 5.38 (s, 2H), 4,98-4,96 (m, 1H), 3.79. -3.77 (m, 1H), 3,69-3,67 (m, 1H), 2,14-2,11 (d, J = 11,6 Hz, 2H), 2,04-2,01 (m, 2H), 1,48-1,41 (m, 4H), 1.38 (s, 6H), 1,32-1,22 (m, 2H), 0,48-0,39 (m , 4H); MS (ESI) m / z 334,3 [M + H]⁺.

Example 30: 4-Cyclobutylamino-2 - (((1R, 4R) -4-metoksitsiklogeksil) amino) pyrimidine-5-carboxamide

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A. 4- (Cyclobutylamino) -2- (methylthio) pyrimidine-5-carbonitrile. To a stirred solution of 4-chloro-2- (methylthio) pyrimidine-5-carbonitrile (2 g, 10.8 mmol) in DMF (10 mL) was added DIEA (4.2 g, 32.4 mmol) and tsiklobutanamin (2, 3 g, 32.4 mmol) at 0 ° C. The resulting mixture was stirred at 60 ° C for 2 hours. The reaction mixture was poured into saturated sodium chloride and extracted with ethyl acetate three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give crude product. The crude product was purified through silica gel column chromatography (10% ethyl acetate in petroleum ether) to give the desired product as a white solid (1.7 g, 7.7 mmol, 71% yield). MS (ESI) m / z = 221,2 [M + H]⁺.

B. 4- (Cyclobutylamino) -2- (metilsulyfinil) pyrimidine-5-carbonitrile and 4- (cyclobutylamino) -2- (metilsulyfonil) pyrimidine-5-carbonitrile. 4- (Cyclobutylamino) -2- (methylthio) pyrimidine-5-carbonitrile (1.7 g, 7.7 mmoly) rastvoryali in DCM (30 ml) and cooled to 0 ° C. K эtoy mixtures portsiyami dobavlyali mCPBA (4,6 g, 23 mmoly) and reaktsionnuyu smesy peremeshivali over 1 h. Poluchennuyu smesy vыlivali in nasыshtennыy vodnыy simply entails bicarbonate sodium. Vodnыy layer эkstragirovali three rasa DCM. Obaedinennыe organicheskie sloi dried over bezvodnыm sulyfatom sodium, filytrovali and kontsentrirovali with polucheniem mixtures 4- (cyclobutylamino) -2- (metilsulyfinil) pyrimidine-5-carbonitrile and 4- (cyclobutylamino) -2- (metilsulyfonil) pyrimidine-5-carbonitrile in Vide zheltogo zhirnogo oil (1.6 g sыroy) kotorыy ispolyzovali in sleduyushtey stages without dopolnitelynoy purification. MS (ESI) m / z = 237,2 / 253,2 [M + H]⁺.

C. 4- (Cyclobutylamino) -2 - (((1R, 4R) -4-metoksitsiklogeksil) amino) pyrimidine-5-carbonitrile. K mixtures 4- (cyclobutylamino) -2- (metilsulyfinil) pyrimidine-5-carbonitrile and 4- (cyclobutylamino) -2- (metilsulyfonil) pyrimidine-5-carbonitrile (1.6 g, sыroy) around predыdushtey stages dobavlyali (1R, 4R) -4-metoksitsiklogeksanamin (0.96 g, 7.4 mmoly), 1,4-dioxane (100 ml) and DIЭA (4.3 g, 33.4 mmoly). Poluchennuyu smesy peremeshivali at 100 ° C for nochi. Then succeeded Vseh letuchih rastvoriteley at ponizhennom davlenii, tverdыy ostatok ochishtali with pomoshtyyu chromatographies of the column to silikagelem (33,3% эtilatsetat in petroleynom эfire) with polucheniem tselevogo product Vide belogo tverdogo substance (1.3 g, 57% vыhod). MS (ESI) m / z = 302,1 [M + H]⁺.

D. 4- (Cyclobutylamino) -2 - (((1 R, 4R) -4-metoksiciklogeksil) amino) pyrimidine-5-carboxamide. To a mixture of 4- (cyclobutylamino) -2 - (((1 R, 4R) -4-metoksiciklogeksil) amino) pyrimidine-5-carbonitrile (700 mg, 2.3 mmol) in DMSO (8 ml) solution Water dobavlâli perekisi vodoroda (1.3 g, 30%, 11.5 mmol), and then a solution of gidroksida Water Sodium (2 ml, 6 mol / l, 11.5 mmol). Peremešivali mix at 50 ° C in a week 0.5 h, then mix in reakcionnuû dobavlâli water (30 ml), the product was dried and gathering place with receipt celevogo Connection (400 mg, 1.25 mmol, 54% output).¹H-ЯМР (400 МГц, CDCl₃) Δ hr. / Million 8.76 (s, 1H), 8.11 (s, 1H), 5.46 (s, 2H), 5.01 (s, 1H), 4,51-4,45 ( m, 1H), 3,83-3,81 (m, 1H), 3.36 (s, 3H), 3.21-3.16 (m, 1H), 2,40-2,33 (m, 2H), 2,15-1,96 (m, 6H), 1.78 (s, 2H), 1,43-1,20 (m, 4H); MS (ESI) m / z = 319,9 [M + H]⁺).

EXAMPLE 31 4- (Cyclobutylamino) -2 - (((1 R, 4R) -4-gidroksiciklogeksil) amino) pyrimidine-5-carboxamide

<img file="00000134.jpg" he="32" wi="53" img-format="tif" img-content="undefined" />

A. 4- (Cyclobutylamino) -2- (metilsulyfinil) pyrimidine-5-carbonitrile and 4- (cyclobutylamino) -2- (metilsulyfonil) pyrimidine-5-carbonitrile. 4- (Cyclobutylamino) -2- (methylthio) pyrimidine-5-carbonitrile (889 mg, 4.04 mmoly; synthesis described in the present activities as described) rastvoryali in DCM (20 mL) and cooled to 0 ° C. K эtoy mixtures portsiyami dobavlyali mCPBA (2,1 g, 12,1 mmoly) and reaktsionnuyu smesy peremeshivali over 1 h. Poluchennuyu smesy vыlivali in nasыshtennыy vodnыy simply entails bicarbonate sodium. Vodnыy layer эkstragirovali three rasa DCM. Obaedinennыe organicheskie sloi dried over bezvodnыm sulyfatom sodium, filytrovali and kontsentrirovali with polucheniem mixtures 4- (cyclobutylamino) -2- (metilsulyfinil) pyrimidine-5-carbonitrile and 4- (cyclobutylamino) -2- (metilsulyfonil) pyrimidine-5-carbonitrile in Vide zheltogo maslyanogo oil (893 mg sыroy) which was used in the next step without further purification. MS (ESI) m / z = 237,2 / 253,2 [M + H]⁺.

B. 4- (Cyclobutylamino) -2 - (((1R, 4R) -4-gidroksitsiklogeksil) amino) pyrimidine-5-carbonitrile. K mixtures 4- (cyclobutylamino) -2- (metilsulyfinil) pyrimidine-5-carbonitrile and 4- (cyclobutylamino) -2- (metilsulyfonil) pyrimidine-5-carbonitrile (424 mg, about 1.93 mmoly) around predыdushtey stages dobavlyali ( 1R, 4R) -4-aminotsiklogeksanol (244 mg, 2.12 mmoly), 1,4-dioxane (50 ml) and DIЭA (1.2 g, 9.65 mmoly). Poluchennuyu smesy peremeshivali at 100 ° C for nochi. Then succeeded Vseh letuchih rastvoriteley at ponizhennom davlenii, tverdыy ostatok ochishtali with pomoshtyyu chromatographies of the column to silikagelem (50% эtilatsetat in petroleynom эfire) with polucheniem tselevogo product Vide belogo tverdogo substances (305 mg, 1.06 mmoly, 55.4% vыhod ). MS (ESI) m / z = 288,2 [M + H]⁺.

C. 4- (Cyclobutylamino) -2 - (((1R, 4R) -4-hydroxycyclohexyl) amino) pyrimidine-5-carboxamide. To a solution of 4- (cyclobutylamino) -2 - (((1R, 4R) -4-hydroxycyclohexyl) amino) pyrimidine-5-carbonitrile (305 mg, 1.06 mmol) in DMSO (6 mL) was added an aqueous solution of hydrogen peroxide (600.1 mg, 30%, 5.3 mmol) and then aqueous sodium hydroxide solution (1 ml, 6 mol / l, 5.3 mmol). The mixture was stirred at 50 ° C for 0.5 hours and then water was added, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and filtered. Concentration under reduced pressure gave a crude product which was purified by chromatography on a silica gel column (0-10% methanol in DCM) to afford compound the title compound (248.2 mg, 0.81 mmol, 76.6% yield) .¹H-ЯМР (400 МГц, CDCl₃) Δ hr. / Million 8.74 (s, 1H), 8.12 (s, 1H), 5.46 (br. S, 2H), 5,07-4,96 (m, 1H), 4, 53-4,43 (m, 1H), 3,80-3,79 (m, 1H), 3.70-3.65 (m, 1H), 2,40-2,34 (m, 2H), 2,15-1,97 (m, 6H), 1,91-1,88 (s, 2H), 1,55-1,19 (m, 4H); MS (ESI) m / z = 306,0 [M + H]⁺.

Example 32: 2- (tert-butylamino) -4 - ((1R, 3R, 4R) -3-gidroksi-4-metilciklogeksilamino) pyrimidine-5-carboxamide

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A. (R) -t-butyl-4-methylcyclohex-3-enilkarbamat and (S) -tert-butyl-4-methylcyclohex-3-enilkarbamat. To a stirred solution of a mixture of (R) -4-methylcyclohex-3-enamine and (S) -4-methylcyclohex-3-enamine (40.2973 g, 359 mmol; prepared as described in J. Org Chem 1992, 57,.. 3454-3462) in ethyl ether (498 ml) at 0 ° C was added dropwise a solution of di-tert-butyl dicarbonate (81 g, 362 mmol) in ethyl ether (100 ml) for 30 min. The reaction mixture was stirred at 0 ° C for 1 hour, allowed to slowly warm to room temperature over 4 h and then stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to give a crude solid. The crude solid was triturated with hexane (500 mL), stirred for 5 min at 0 ° C, then filtered and washed with hexane (50 ml) to give the first batch of product (~ 55 g). The filtrate was concentrated under reduced pressure, triturated with hexane, and the residue was filtered to give a second batch of product (~ 15 g). The process was repeated to give a third batch (4.25 g). Three batches were combined to obtain a mixture (R) -tert-butyl-4-methylcyclohex-3-enilkarbamata and (S) -tert-butyl-4-methylcyclohex-3-enilkarbamata (74.25 g, 351 mmol, 98% yield) as a white solid.¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 6.72 (d, J = 7,42 Hz, 1H), 5.26 (br. S., 1H), 3.35-3.47 (m, 1H), 1.93 (br. s., 5H), 1.60 (s, 3H), 1.32-1.44 (m, 10H).

B. Tert-butyl (1R, 3R, 4R) -3-hydroxy-4-metiltsiklogeksilkarbamat, tert-butyl (1R, 3S, 4S) -3-hydroxy-4-metiltsiklogeksilkarbamat, tert-butyl (1S, 3R , 4R) -3-hydroxy-4-metiltsiklogeksilkarbamat, tert-butyl (1S, 3S, 4S) -3-hydroxy-4-metiltsiklogeksilkarbamat. To a stirred solution of a mixture of (R) -tert-butyl-4-methylcyclohex-3-enilkarbamata and (S) -tert-butyl-4-methylcyclohex-3-enilkarbamata (13 g, 61.6 mmol) in THF (780 ml) at 0 ° C was added 1 M borane THF complex (277 ml, 277 mmol). The solution was stirred at 0 ° C, allowed to warm to room temperature over 1 h, and then stirred at room temperature for 20 hours. The reaction mixture was slowly quenched with water (330 ml), diluted with ethanol (326 ml) and acidified with 5N aqueous solution of sodium hydroxide (308 ml, 1.54 mol). To a stirred two-phase mixture was slowly added 30% hydrogen peroxide (316 mL, 3.08 mol) and the resulting mixture was heated to 45 ° C for 20 hours. The crude reaction mixture was quenched with a saturated aqueous solution of sodium sulfite (573 mL) and extracted with ethyl acetate ( 4 × 1 l). The combined organic layers were washed with saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give crude product. The above reaction was repeated 5 times (using 13 g of 3 × 2 × 11 g of starting material). The combined crude products from reaction mixtures 6 was purified by silica gel chromatography (0-100% ethyl acetate in hexane). Fractions containing product were combined and concentrated under reduced pressure to give a mixture of tert-butyl (1R, 3R, 4R) -3-hydroxy-4-metiltsiklogeksilkarbamata, tert-butyl (1R, 3S, 4S) -3-hydroxy-4-metiltsiklogeksilkarbamata, tert-butyl (1S, 3R, 4R) -3-hydroxy-4-metiltsiklogeksilkarbamata and tert-butyl (1S, 3S, 4S) -3-hydroxy-4-metiltsiklogeksilkarbamata (55 g, 242 mmol, 72% yield) as a solid. 4 stereoisomers components were removed using preparative chiral SFC, using multiple injections in a series of three separate columns. First column: ChiralPak AD-H, 250 × 50 mm ID, isocratic 35% methanol in CO₂. Second column: ChiralPak AD-H, 250 × 50 mm ID, isocratic 25% methanol in CO₂. Third column: ChiralPak AD-H, 250 × 50 mm ID, isocratic 15% ethanol in CO₂. The separated isomers were characterized on column ChiralPak AD-3 150 × 4,6 mm ID, 5-40% methanol (containing 0.05% diethylamine) to CO₂ (Run time 15 min) on an analytical scale, and was designated as Intermediate 1 - Intermediate 4.

Intermediate 1 2.0 g (8.72 mmol, 3.6% yield from the SFC purification). Retention time: 4.77 minutes. MS (ESI) m / z 252,1 [M + 23]⁺.

Intermediate 2: 1.5 g (6.54 mmol, 2.7% yield from the SFC purification). Retention time: 5.08 minutes. MS (ESI) m / z 252,1 [M + 23]⁺.

Intermediate 3: 16.0 g (69.78 mmol, 29.1% yield of SFC purification). Retention time: 5.48 minutes.¹Н-ЯМР (400 МГц, DMCO-d₆) Δ hr. / Million 6,64-6,86 (m, 1H), 4,43-4,60 (m, 1H), 3,10-3,29 (m, 1H), 2,81-2 96 (m, 1H), 1.84-2.01 (m, 1H), 1,49-1,72 (m, 2H), 1.37 (s, 9H), 0,98-1,14 (m, 3H), 0,76-0,96 (m, 4H). MS (ESI) m / z 252,1 [M + 23]⁺.

Intermediate 4: 18.5 g (80.68 mmol, 33.6% yield of SFC purification). Retention time: 7.79 minutes. MS (ESI) m / z 252,1 [M + 23]⁺.

Low molecular X-ray crystal structure analysis was performed for the intermediate 3, and, as shown, the structure is tert-butyl (1R, 3R, 4R) -3-hydroxy-4-metiltsiklogeksilkarbamat. X-ray analysis was as follows. Single-crystal X-ray diffraction analyzes were performed on diffractometer Bruker Kappa APEX CCD, equipped with a Cu K_a radiation (λ = 1,5478). Crystals of the title compound were grown by vapor diffusion of hexane in the solution phase hexane / THF. Beztsvetnye crystals of 0.21 × 0.05 × 0.03 mm was mounted on Cryoloop with Paratone oil. Data was collected in a nitrogen gas stream at 120 (2) K, using scanning and φ<img file="00000136.jpg" he="4" wi="4" img-format="tif" img-content="undefined" />. A distance from the crystal to detector were 60 mm using a variable exposure time (2 - 20) depending on the width θ with the scanning 1,0 °. Data collection was completed in 97.0% to 68,00 ° in θ. A total of 9000 reflections were collected covering codes, -33 &lt;= h &lt;= 32 31 &lt;= k &lt;= 30, -6 &lt;= 1 &lt;= 5. It was found that the 2554 independent reflections have symmetry with R_int of 0.0602. Indexing and milling unit cell indicating a rhombohedral, hexagonal lattice. It has been found that the space group is R3. Data were integrated using the Bruker SAINT and scaled using SADABS software software. Solution by direct methods (SHELXS) gave complete phase model corresponding to the structure of tert-butyl (1R, 3R, 4R) -3-hydroxy-4-metiltsiklogeksilkarbamat.

All non-hydrogen atoms were refined anisotropically using the full-least-squares method (SHELXL-97). All hydrogen atoms were placed in a riding model. Their positions were limited relative to the parent atom, using the appropriate command in HFIX SHELXL-97.

C. (1R, 2R, 5R) -5-Amino-2-methylcyclohexanol hydrochloride. To a vigorously stirred methanol (149 ml) at 0 ° C was added acetyl chloride (15.87 ml, 223 mmol) and the resulting mixture was stirred for 10 min. To this solution were added tert-butyl (1R, 3R, 4R) -3-hydroxy-4-metiltsiklogeksilkarbamat (17.08 g, 74.5 mmol) and the mixture was stirred for 22 hours at room temperature. The crude reaction mixture was concentrated and then triturated with ethyl ether (2 × 300 ml) to give the hydrochloride of (1R, 2R, 5R) -5-amino-2-methylcyclohexanol (12.2 g, 73.6 mmol, 99% yield ) as a white solid.¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8.02 (br. S., 3H), 4.77 (d, J = 5,86 Hz, 1H), 2.85-3.10 (m, 2H), 2.03 -2.21 (m, 1H), 1.83 (d, J = 11,71 Hz, 1H), 1.65 (dd, J = 13.47, 3.32 Hz, 1H), 1.24 ( q, J = 11,58 Hz, 2H), 1.12 (dd, J = 6.05, 3.32 Hz, 1H), 0,82-1,03 (m, 4H).

D. 5-Bromo-N-tert-butyl-4- (methylthio) pyrimidin-2-amine. To 5-bromo-2-chloro-4- (methylthio) pyrimidine (3 g, 12.53 mmol) in dioxane (12.53 mL) was added 2-methylpropan-2-amine (7.93 mL, 75 mmol). The mixture was stirred at 100 ° C overnight in a sealed vessel. The solvent was removed under reduced pressure and the solid residue was dissolved in 100 mL ethyl acetate and washed with 50 ml of 1M aqueous sodium dihydrogen phosphate. The aqueous layer was again extracted with 50 ml of ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated to give 5-bromo-N-tert-butyl-4- (methylthio) pyrimidin-2-amine (3.4 g, 12.31 mmol, 98% yield) as a solid.¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8,61-8,72 (m, 1H), 8.08 (s, 1H), 6,95-7,17 (m, 1H), 2.48 (s, 2H) 1.38 (s, 9H). MS (ESI) m / z 276,0 [M + 1]⁺and 278.2 [M + 1]⁺.

E. 2- (tert-butylamino) -4- (methylthio) pyrimidine-5-carbonitrile. 5-Bromo-N-tert-butyl-4- (methylthio) pyrimidine-2-amine (3400 mg, 12.31 mmolь) cinkovuю pыlь (201 mg, 3.08 mmolь), zinc cyanide (940 mg, 8 00 mmolь), 1,1'-bis (diphenylphosphino) ferrocen (552 mg, 0.985 mmolь), tris (dibenzylideneacetone) dipalladiй (0) (564 mg, 0.616 mmolь) and DMF (20.5 mL) and heated at obъedinяli at 90 ° C in a nitrogen atmosphere nochi. Reakcionnuю smesь razbavlяli эtilacetata 125 ml and 50 ml vodы and zatem filьtrovali cherez decline throughout. Layered filьtrata manure removal and vodnый layer эkstragirovali 75 ml эtilacetata. Obъedinennыe эtilacetat sloi promыvali 2 × 50 ml nasыщennыm solevыm rastvorom, dried bezvodnыm sulьfatom tycoon filьtrovali and koncentrirovali to oils in ponizhennom davlenii.¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8,37-8,51 (m, 1H), 7.85-8.10 (m, 1H), 2.53-2.62 (m, 3H), 1.41 (s 9H). MS (ESI) m / z 223,1 [M + 1]⁺.

F. 2- (tert-butylamino) -4- (methylthio) pyrimidine-5-carboxamide. K peremeshivaemomu solvent 2- (tert-butylamino) -4- (methylthio) pyrimidine-5-carbonitrile (0.6 g, 2.70 mmolь) in DMSO (7 ml) solution dobavlяli vodnый gidroksida 6M sodium (2.249 mL, 13 mmolь 49) and 30% hydrogen perekisni vodnый solution (1.530 ml, 13.49 mmolь) at 0 ° C. Zatem smesь peremeshivali at 50 ° C for 15 min. Reakcionnuю smesь vыlivali in vodu (40 ml) and эkstragirovali эtilacetatom (3 × 50 mL). Obъedinennыe organicheskie sloi promыvali nasыщennыm solevыm rastvorom, dried bezvodnыm sulьfatom sodium and filьtrovali. Koncentrirovanie filьtrata in ponizhennom davlenii sыroй yielded a product with kotorый ochiщali pomoщью chromatography columns silikagelem (5% methanol in DCM) to polucheniem 2- (tert-butylamino) -4- (methylthio) pyrimidine-5-carboxamide (0.462 g, 1.922 mmolь, 71, 2% yield) as a white solid. MS (ESI) m / z 241,0 [M + 1]⁺.

G. 2- (t-butylamino) -4- (metilsulьfinil) pyrimidine-5-carboxamide. K peremeshivaemomu solvent 2- (tert-butylamino) -4- (methylthio) pyrimidine-5-carboxamide (0.1 g, 0.416 mmolь) in chloroform (12 ml) porciяmi dobavlяli 3-phenyl-2- (fenilsulьfonil) -1 2-oxaziridine (0.130 g, 0.499 mmolь). Poluchennый light zheltый peremeshivali solution at okruzhaющeй sredы over nochi. Reakcionnый koncentrirovali solution in ponizhennom davlenii with polucheniem sыrogo product belogo saw tverdogo substances. Dobavlяli эtilacetat (1 ml), and the vzvesь peremeshivali komnatnoй temperature for 1 h. Tverdыe filьtrovali substances, promыvali эtilacetatom and dried in vacuum to polucheniem 2- (tert-butylamino) -4- (metilsulьfinil) pyrimidine-5-carboxamide (0 092 g, 0.359 mmolь, vыhod 86%). MS (ESI) m / z 257,3 [M + 1]⁺.

N. 2- (tert-butylamino) -4 - ((1R, 3R, 4R) -3-hydroxy-4-methylcyclohexylamine) pyrimidine-5-carboxamide. To a stirred suspension of 2- (tert-butylamino) -4- (methylsulfinyl) pyrimidine-5-carboxamide (0.092 g, 0.359 mmol) and hydrochloride of (1R, 2R, 5R) -5-amino-2-methylcyclohexanol (0.065 g, 0.395 mmol) in DMF (2 mL) was added N-ethyl-N-izopropilpropan-2-amine (0.157 mL, 0.897 mmol) and the reaction mixture was heated to 90 ° C overnight. The crude reaction mixture was concentrated under reduced pressure, and then the solid residue was added to ice water (20 ml). The resulting mixture was stirred vigorously for 1 h and then the product was filtered, washed with water and dried in vacuo to give 2- (tert-butylamino) -4 - ((1R, 3R, 4R) -3-hydroxy-4-methylcyclohexylamine) pyrimidine 5-carboxamide (0.074 g, 0.230 mmol, 64.1% yield).¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8.94 (br. S., 1H), 8.34 (s, 1H), 6.69 (br. S., 1H), 4.59 (d, J = 5,47 Hz, 1H), 3.87 (br. s., 1H), 2.92-3.01 (m, 1H), 2.14 (d, J = 10,15 Hz, 1H), 1.91 ( d, J = 11,71 Hz, 1H), 1.67 (dd, J = 13.28, 3.12 Hz, 1H), 1,07-1,24 (m, 3H), 0,91-0 99 (m, 4H). MS (ESI) m / z 322,3 [M + 1]⁺.

Example 33: 2- (Cyclopropylamino) -4 - ((1R, 3R, 4R) -3-gidroksi-4-metiltsiklogeksilamino) pyrimidine-5-carboxamide

<img file="00000137.jpg" he="40" wi="44" img-format="tif" img-content="undefined" />

A. 2- (cyclopropylamino) -4 - ((1R, 3R, 4R) -3-gidroksi-4-metiltsiklogeksilamino) pyrimidine-5-carbonitrile. K rastvoru 4 - ((1R, 3R, 4R) -3-gidroksi-4-metiltsiklogeksilamino) -2- (metilsulyfonil) pyrimidine-5-carbonitrile (362 mg, 1,166 mmoly; synthesis described in the present activities as described) in NMP (5,832 ml ) dobavlyali cyclopropanamine (0.485 ml, 7.00 mmoly). Reaktsionnuyu smesy peremeshivali at 80 ° C for 5 hours in germeticheski zakrыtom Dewar and zatem ostavlyali ohlazhdatysya to temperaturы okruzhayushtey sredы over nochi. Reaktsionnuyu smesy kontsentrirovali at ponizhennom davlenii to oils kotoroe ochishtali with pomoshtyyu chromatographies on silica gel (0-60% эtilatsetat / Gexto) with polucheniem 2- (cyclopropylamino) -4 - ((1R, 3R, 4R) -3-gidroksi-4- metiltsiklogeksilamino) pyrimidine-5-carbonitrile (265 mg, 0.922 mmoly, 79% vыhod) in Vide tverdogo substances.¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 6,99-8,32 (m, 3H), 4.54 (d, J = 5,08 Hz, 1H), 3,85-4,13 (m, 1H), 2, 80-3,03 (m, 1H), 2,58-2,75 (m, 1H), 1,50-2,08 (m, 3H), 1,03-1,42 (m, 3H), 0.88 (d, J = 6,25 Hz, 4H), 0,29-0,68 (m, 4H). MS (ESI) m / z 288,1 [M + 1]⁺.

B. 2- (cyclopropylamino) -4 - ((1R, 3R, 4R) -3-gidroksi-4-metiltsiklogeksilamino) pyrimidine-5-carboxamide. 2- (Cyclopropylamino) -4 - ((1R, 3R, 4R) -3-gidroksi-4-metiltsiklogeksilamino) pyrimidine-5-carbonitrile (265 mg, 0.922 mmoly) rastvoryali in DMSO (9,222 ml). K rastvoru dobavlyali 10 kapely 50% vodnogo simply entails gidroksida sodium and zatem 10 kapely 30% vodnogo simply entails perekisni hydrogens on komnatnoy temperature. Poluchennuyu reaktsionnuyu smesy peremeshivali at 50 ° C for 2 h and zatem medlenno dobavlyali in 60 ml ledyanoy vodы. Poluchennыy ostatok peremeshivali within 30 minutes filytrovali and promыvali water. Tverdыe substances dried vakuumnoy Pechi over nochi at 45 ° C with polucheniem 2- (cyclopropylamino) -4 - ((1R, 3R, 4R) -3-gidroksi-4-metiltsiklogeksilamino) pyrimidine-5-carboxamide (229 mg, 0.750 mmoly, 81% vыhod).¹H-NMR (400 MHz, DMSO-d₆) Δ h. / M 8,73-8,95 (m, 1H), 8,18-8,42 (m, 1H), 7,17-7,37 (m, 1H), 4,39-4 62 (m, 1 H), 3,75-3,99 (m, 1H), 2,81-3,06 (m, 1H), 2,53-2,74 (m, 1H), 2.09 -2.34 (m, 1H), 1,82-2,05 (m, 1H), 1,50-1,69 (m, 1H), 0,99-1,24 (m, 3H), 0 , 81-0,98 (m, 4H), 0,50-0,67 (m, 2H), 0,26-0,47 (m, 2H). MS (ESI) m / z 306,3 [M + 1]⁺.

Example 34: 2- (tert-butylamino) -4 - ((1R, 3R) -3-gidroksi-4,4-dimetilciklogeksilamino) pyrimidine-5-carboxamide

<img file="00000138.jpg" he="41" wi="43" img-format="tif" img-content="undefined" />

A. 4,4-dimethyl-cyclohex-2-enol. Sodium borohydride (5.03 g, 133 mmol) was added portionwise to a stirred solution of 4,4-dimethyl-cyclohex-2-enone (15.0 g, 121 mmol) in methanol (403 mL) in a water bath. After complete addition the solution was allowed to stir under nitrogen at room temperature for 3 hours. The reaction mixture was diluted with water (150 mL) and most of the methanol was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate (2 × 200 mL). The combined ethyl acetate extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to an oil under reduced pressure to give 4,4-dimethyl-cyclohex-2-enol (13.4 g, 106 mmol, 88% yield).¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 5,41-5,57 (m, 1H), 5,24-5,42 (m, 1H), 4.61 (d, J = 5,47 Hz, 1H), 3, 82-3,99 (m, 1H), 1.65-1.83 (m, 1H), 1,21-1,59 (m, 3H), 0.93 (d, J = 15,23 Hz, 6H).

B. 2- (4,4-dimethyl-cyclohex-2-enyl) isoindoline-1,3-dione. Triphenylphosphine to a polymeric substrate (32.7 g, 106 mmol), isoindoline-1,3-dione (17.19 g, 117 mmol) and 4,4-dimethyl-cyclohex-2-enol (13.4 g, 106 mmol) were combined and added THF (197 mL). The mixture was stirred and cooled to 0 ° C, then added dropwise diisopropyl azodicarboxylate (21.09 mL, 107 mmol) over 2 min. The reaction mixture was stirred and allowed to warm slowly to ambient temperature overnight. The reaction mixture was filtered and then concentrated to a yellow solid under reduced pressure. Ethyl acetate (200 mL) and the resulting solids were filtered off again. Ethyl acetate filtrate was washed with water (100 ml), the aqueous layer was extracted with ethyl acetate (100 mL) and the combined organic layers were dried over anhydrous magnesium sulfate, filtered,¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 7.84 (s, 4H), 5,51-5,62 (m, 1H), 5.43 (d, J = 10,15 Hz, 1H), 4,59-4, 74 (m, 1H), 2.14-2.30 (m, 1H), 1.67-1.81 (m, 1H), 1,44-1,68 (m, 2H), 1.09 ( s, 3H), 1.01 (s, 3H); MS (ESI) m / z 256,2 [M + 1]⁺.

C. A mixture of 2 - ((1R, 2S, 3S) -2-bromo-3-hydroxy-4,4-dimethylcyclohexyl) isoindoline-1,3-dione, 2 - ((1S, 2R, 3R) -2-bromo -3-hydroxy-4,4-dimethylcyclohexyl) isoindoline-1,3-dione, 2 - ((1R, 2R, 3R) -3-bromo-2-hydroxy-4,4-dimethylcyclohexyl) isoindoline-1,3- dione, 2 - ((1S, 2S, 3S) -3-bromo-2-hydroxy-4,4-dimethylcyclohexyl) isoindoline-1,3-dione. To a solution of 2- (4,4-dimethyl-cyclohex-2-enyl) isoindoline-1,3-dione (11.59 g, 45.4 mmol) in chloroform (110 ml) and ethanol (3.83 ml) was added N- bromosuccinimide (10.34 g, 58.1 mmol) as a solid for several minutes at ambient temperature. After the addition was complete, the reaction mixture was stirred at ambient temperature overnight under a nitrogen atmosphere. The reaction mixture was washed with 1 M aqueous sodium thiosulfate (100 mL). The aqueous layer was extracted with chloroform (100 ml) and the combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. To this oil was added 150 mL of THF (150 ml) and 1N. aqueous hydrochloric acid solution (30 mL). The resulting mixture was stirred at ambient temperature for 2 hours, THF was removed under reduced pressure and the remaining aqueous layer was diluted with ethyl acetate (150 ml) and 75 ml of a 1:. 1 water: saturated aqueous sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted again with an aqueous solution of ethyl acetate (75 mL). The combined ethyl acetate layers were washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to an oil which was purified by silica gel chromatography (0-25% ethyl acetate / hexane) to give a mixture of 2 - ((1R, 2S , 3S) -2-bromo-3-hydroxy-4, 4-dimethylcyclohexyl) isoindoline-1,3-dione, 2 - ((1S, 2R, 3R) -2-bromo-3-hydroxy-4,4-dimethylcyclohexyl) isoindoline-1,3-dione, 2 - ((1R , 2R, 3R) -3-bromo-2-hydroxy-4,4-dimethylcyclohexyl) isoindoline-1,3-dione and 2 - ((1S, 2S, 3S) -3-bromo-2-hydroxy-4,4 -dimetiltsiklogeksil) isoindoline-1,3-dione (11.4 g, 32.4 mmol, 71.3% yield). MS (ESI) m / z 374,5 [M + 1]⁺and 376.5 [M + 1]⁺.

D. A mixture of 2 - ((1R, 3R) -3-hydroxy-4,4-dimethylcyclohexyl) isoindoline-1,3-dione and 2 - ((1S, 3S) -3-hydroxy-4,4-dimethylcyclohexyl) isoindoline -1,3-dione. A mixture of 2 - ((1R, 2S, 3S) -2-bromo-3-hydroxy-4,4-dimethylcyclohexyl) isoindoline-1,3-dione, 2 - ((1S, 2R, 3R) -2-bromo-3 hydroxy-4,4-dimethylcyclohexyl) isoindoline-1,3-dione, 2 - ((1R, 2R, 3R) -3-bromo-2-hydroxy-4,4-dimethylcyclohexyl) isoindoline-1,3-dione and 2 - ((1S, 2S, 3S) -3-bromo-2-hydroxy-4,4-dimethylcyclohexyl) isoindoline-1,3-dione (5.7 g, 16.18 mmol) was dissolved in toluene (90 ml) and methanol (9 mL). To the solution was added tributyltin hydride (5.66 mL, 21.04 mmol) over 10 min via syringe under nitrogen, and then azobisisobutyronitrile (0.266 g, 1.618 mmol) in one portion. The mixture was allowed to stir at reflux under nitrogen overnight.¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 7.82 (s, 4H), 4,51-4,80 (m, 1H), 3,80-4,03 (m, 2H), 2,84-3,11 (m , 1H), 1,49-1,67 (m, 3H), 1.37-1.47 (m, 1H), 1.22-1.35 (m, 1H), 1.13 (s, 3H ), 0.80-0.93 (m, 3H). MS (ESI) m / z 274,0 [M + 1]⁺. small molecule x-ray crystal structure analysis was conducted for the product mixture. X-ray analysis was as follows. Single crystal X-ray diffraction analyzes were performed on diffractometer Bruker Kappa APEX-II CCD, equipped with Mo K_a radiation (λ = 0,71073 <img file="00000139.jpg" he="4" wi="4" img-format="tif" img-content="undefined" />). Crystals were grown by vapor diffusion of pentane into the DCM solution. Beztsvetnye crystals of 0.25 × 0.20 × 0.05 mm was mounted on Cryoloop with Paratone oil. Data was collected in a nitrogen gas stream at 90 (2) K, using scanning and φ<img file="00000140.jpg" he="3" wi="4" img-format="tif" img-content="undefined" />. A distance from the crystal to detector were 60 mm, exposure time 20 on the frame using a scan width of 0,5 °. Data collection was completed by 100% to 25,00 ° in θ. A total of 10827 reflections were collected covering the indices, -21 &lt;= h &lt;= 12, -7 &lt;= k &lt;= 8, -28 &lt;= l &lt;= 29. It was found that the 2892 independent reflections have symmetry with Rint from 0, 0821. Indexing and unit cell refinement indicated a rhombohedral, hexagonal lattice. It has been found that the space group is Pbcn. Data were integrated using the Bruker SAINT and scaled using SADABS software software. Solution by direct methods (SHELXS) gave complete phase model corresponding to a mixture of an enantiomeric pair structure 2 - ((1R, 3R) -3-hydroxy-4,

All non-hydrogen atoms were refined anisotropically using the full-least-squares method (SHELXL-97). All hydrogen atoms were placed in a riding model. Their positions were limited relative to the parent atom, using the appropriate command in HFIX SHELXL-97.

E. A mixture of (1R, 5R) -5-amino-2,2-dimethyl cyclohexanol hydrochloride and the (1S, 5S) -5-amino-2,2-dimethyl cyclohexanol hydrochloride. To a mixture of 2 - ((1R, 3R) -3-hydroxy-4,4-dimethylcyclohexyl) isoindoline-1,3-dione and 2 - ((1S, 3S) -3-hydroxy-4,4-dimethylcyclohexyl) izoindolin- 1,3-dione (1.1 g, 4.02 mmol) in ethanol (50 ml) was added hydrazine hydrate (0.195 mL, 4.02 mmol). The resulting solution was allowed to stir at reflux overnight under nitrogen. The reaction mixture was cooled to ambient temperature and then acidified to pH &lt;2 by addition of concentrated aqueous hydrochloric acid. The residue was filtered, washed with ethanol and then the resulting filtrate was concentrated to 20 ml under reduced pressure. Added an equivalent volume of water, and the mixture was stirred at ambient temperature for 15 min. The solids were filtered, washed with water, and the filtrate was concentrated under reduced pressure to give a solid which was dried in a vacuum oven for several hours to afford a mixture of the hydrochloride (1R, 5R) -5-amino-2,2-dimethylcyclohexanol hydrochloride and (1S , 5S) -5-amino-2,2-dimethylcyclohexanol (835 mg, 4.65 mmol, 115% yield) which was used without further purification.¹Н-ЯМР (400 МГц, DMCO-d₆) Δ h. / M 7,87-8,21 (m, 3H), 2,98-3,23 (m, 1H), 2,75-3,02 (m, 1H), 1,49-1 92 (m, 2H), 1,26-1,47 (m, 3H), 0,96-1,16 (m, 1H), 0,48-0,93 (m, 6H).

F. 2- (tert-butylamino) -4 - ((1R, 3R) -3-gidroksi-4,4-dimetilciklogeksilamino) pyrimidine-5-carboxamide and 2- (tert-butylamino) -4 - ((1S, 3S ) -3-gidroksi-4,4-dimetilciklogeksilamino) pyrimidine-5-carboxamide. K peremeshivaemoй suspensions 2- (tert-butylamino) -4- (metilsulьfinil) pyrimidine-5-carboxamide (375 mg, 1.46 mmolь) and mixtures gidrohlorida (1R, 5R) -5-amino-2,2-dimetilciklogeksanola and gidrohlorida (1S, 5S) -5-amino-2,2-dimetilciklogeksanola (342 mg, 1.902 mmolь) in DMF (4.877 ml) dobavlяli DIЭA (0.767 ml, 4.39 mmolь) reakcionnuю smesь and heated to 90 ° C nochi. Sыruю reakcionnuю smesь koncentrirovali in ponizhennom davlenii and zatem ochiщali, ispolьzuя polipreparativnuю VЭZHH convertibility with a phase (5-80% acetonitrile + 0.1% TFU in water + 0.1% TFU, over 30 min). Fractions soderzhaщie product concentrated under reduced pressure and dissolved again in ethyl acetate (125 mL) and a saturated aqueous solution of sodium bicarbonate (50 ml). The layers was removed and the aqueous layer was extracted with ethyl acetate (75 mL). The combined ethyl acetate layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting solid was again dissolved in methanol (5 ml) was passed through a SPE tube with a Varian StratoSpheres HCO3 polymer to remove TFA (0.9 mmol bicarbonate equiv.), And then concentrated under reduced pressure to give an oil which was triturated with diethyl ether and again concentrated to afford solids. The solids are dried for several hours in a vacuum oven at 45 ° C to give a mixture of 2- (tert-butylamino) -4 - ((1R, 3R) -3-hydroxy-4,

G. Separation SFC mixture of 2- (tert-butylamino) -4 - ((1R, 3R) -3-hydroxy-4,4-dimethylcyclohexylamine) pyrimidine-5-carboxamide and 2- (tert-butylamino) -4 - (( 1S, 3S) -3-hydroxy-4,4-dimethylcyclohexylamine) pyrimidine-5-carboxamide. The mixture of enantiomers of 2- (tert-butylamino) -4 - ((1R, 3R) -3-hydroxy-4,4-dimethylcyclohexylamine) pyrimidine-5-carboxamide and 2- (tert-butylamino) -4 - ((1S, 3S ) -3-hydroxy-4,4-dimethylcyclohexylamine) pyrimidine-5-carboxamide (373 mg) was separated by preparative chiral SFC, using a column ChiralPak AD-H, 250 × 30 mm ID with isocratic 32% ethanol + 0.1% ammonium hydroxide in CO₂ gradient at a flow rate of 50 ml / min. The isomer eluted faster, was designated as peak 1 and 155 mg (0.462 mmol) was obtained. The isomer eluted slower was labeled as peak 2 and 170.0 mg (0.502 mmol) was obtained. Peak 1:¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8,82-9,11 (m, 1H), 8.34 (s, 1H), 6,50-6,82 (m, 1H), 4,40-4,72 (m , 1H), 3,72-4,01 (m, 1H), 3,01-3,25 (m, 1H), 1.83-1.99 (m, 1H), 1.65-1.81 (m, 1H), 1.37 (s, 13H), 0,89-0,95 (m, 3H), 0,72-0,88 (m, 3H). MS (ESI) m / z 336,2 [M + 1]⁺. Peak 2:¹H-NMR (400 MHz, DMSO-d₆) Δ 8,95 (s, 1H), 8.34 (s, 1H), 6.68 (s, 1H), 4.52 (d, J = 4,9 Hz, 1H), 3.86 (s , 1H), 3.15 (dt, J = 11.3, 4.6 Hz, 1H), 1.90 (d, J = 11,9 Hz, 1H), 1.72 (s, 1H), 1 40 (s, 1H), 1.36 (s, 9H), 1,34-1,05 (m, 3H), 0.91 (s, 3H), 0.82 (s, 3H). MS (ESI) m / z 336,2 [M + 1]⁺. By comparing the SAR forces with similar compounds of known absolute stereochemistry, as set forth herein, peak 1 was identified as 2- (tert-butylamino) -4 - ((1S, 3S) -3-hydroxy-4,4-dimethylcyclohexylamine ) pyrimidine-5-carboxamide. Peak 2 was identified as 2- (tert-butylamino) -4 - ((1R, 3R) -3-hydroxy-4,4-dimethylcyclohexylamine) pyrimidine-5-carboxamide.

Example 35: 2 - ((1R, 4R) -4-Gidroksiciklogeksilamino) -4- (isopropylamino) pyrimidine-5-carboxamide

<img file="00000141.jpg" he="28" wi="54" img-format="tif" img-content="undefined" />

A. Эtil-4- (isopropylamino) -2- (methylthio) pyrimidine-5-carboxylate. Эtil-4-chloro-2- (methylthio) pyrimidine-5-carboxylate (900 g, 3.87 moly) эtanol (12 l), DIЭA (876 mL, 5.05 moly) and isopropylamine (379 ml, 4 45 moly) obaedinyali and smeshivali at temperatures okruzhayushtey sredы over 4 h. Dobavlyali dopolnitelynuyu portsiyu amounts of isopropylamine (50 mL, 0.59 moly) and smesy peremeshivali over nochi at temperatures okruzhayushtey sredы. Reaktsionnuyu smesy kontsentrirovali at ponizhennom davlenii and sыroy product razbavlyali water (2 L). Vodnыy layer эkstragirovali hloroformom (2 × 3 L). Obaedinennыe organicheskie sloi dried over bezvodnыm sulyfatom Magna, filytrovali and kontsentrirovali at ponizhennom davlenii with polucheniem эtil-4- (isopropylamino) -2- (methylthio) pyrimidine-5-carboxylate (1042, 4.08 moly,&gt; 100% vыhod, contaminated with trace amounts of DIEA) as a pale brown oil which was used without further purification. MS (ESI) m / z 256,4 [M + 1]⁺.

V. 4- (Isopropylamino) -2- (methylthio) pyrimidine-5-karbonovaâ acid. Ethyl-4- (isopropylamino) -2- (methylthio) pyrimidine-5-carboxylate (1042 g, 4.08 mol,&gt; 100%, zagrâznen sledovymi količestvami DIEA) rastvorâli in ethanol (10 l), and to the solution polučennomu dobavlâli 2M Water Sodium gidroksida solution (3.87 l, 7.74 mol). Polučennuû mix peremešivali the week at night Ambient temperature and then koncentrirovali in ponižennom pressure. Received tverdoe substance razbavlâli 2 l of water and then promyvali methyl-tert-butilovym EFIR (2 × 1.2 L). rN podkislâli to water layer until pH 4.2-4.5 via 2n hloristovodorodnoj to water solution of acids. The obtained Solid substances gathering place via filtration, washed with water (2 L) and hexane (2 L) and then dried overnight in a vacuum oven at 45 ° C to give 4- (isopropylamino) -2- (methylthio) pyrimidine-5-carboxylic acid (848 g, 96, 5% yield over 2 steps) as an off-white solid. MS (ESI) m / z 228,1 [M + 1]⁺.

C. 4- (Isopropylamino) -2- (methylthio) pyrimidine-5-carboxamide. To a solution of 4- (isopropylamino) -2- (methylthio) pyrimidine-5-carboxylic acid (180 g, 0.792 mol) and HOBt (123 g, 0.911 mol) in anhydrous THF (6.9 L) was added dropwise to a mixture of EDC ( 174.6 g, 0.911 mol) in acetonitrile (3.7 l) at ambient temperature. The mixture was stirred for 1 hour at ambient temperature and then dropwise added aqueous solution of ammonium hydroxide (989 mL, 28-30% concentrated, 10 eq.) For 30 min. The resulting mixture was heated with gentle reflux for 3 hours and then concentrated under reduced pressure. The residual solid was diluted with a saturated aqueous sodium bicarbonate (5 liters) and then extracted twice with ethyl acetate (9 L and 2 L, respectively). The combined organic layers were washed with saturated aqueous sodium bicarbonate (4 l), water (4 L), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4- (isopropylamino) -2- (methylthio) pyrimidine-5-carboxamide (171.2 g, 95.5% yield) as a solid. MS (ESI) m / z 227,4 [M + 1]⁺.

D. 4- (isopropylamino) -2- (methylsulfinyl) pyrimidine-5-carboxamide. To a solution of 4- peremešivaemomu (isopropylamino) -2- (methylthio) pyrimidine-5-carboxamide (170 g, 0.751 mol) in chloroform (22 l) Porcia dobavlâli 3-phenyl-2- (phenylsulfonyl) -1,2-oxaziridine ( 235.6 g, 0.902 mol), and a solution of peremešivali recieved at Ambient temperature in week overnight. Dobavlâli additional Porcia 3-phenyl-2- (phenylsulfonyl) -1,2-oxaziridine (19.6 g, 0.075 mol), and the mixture then peremešivali in week overnight at Ambient temperatures. Reakcionnyj solution koncentrirovali in ponižennom pressure syrogo with receipt of the product in the form of a rigid white substances. Solid substances nasyŝali ethyl acetate (1.5 l) at Ambient Temperature in week 1 h, filʹtrovali, washed with ethyl acetate (250 ml) and dried in a vacuum oven overnight at 45 ° C to give 4- (isopropylamino) -2- (methylsulfinyl) as a white solid pyrimidin-5-carboxamide (167.7 g, 92% yield) substances. MS (ESI) m / z 243,2 [M + 1]⁺.

E. 2 - ((1R, 4R) -4-hydroxycyclohexylamino) -4- (isopropylamino) pyrimidine-5-carboxamide. A mixture of (1R, 4R) -4-aminocyclohexanol (262.4 g, 2.278 mol) and anhydrous DMF (79 mL) was heated to 100 ° C. To this mixture was added portionwise 4- (isopropylamino) -2- (methylsulfinyl) pyrimidine-5-carboxamide (157.7 g, 0.651 mol). The resulting mixture was allowed to stir under nitrogen at 110 ° C overnight. The reaction mixture was concentrated under reduced pressure to remove DMF. To the residual solid was added water (2 L), and the mixture was extracted with ethyl acetate (3 × 2 L). The combined organic extracts were washed with water (2 × 2 L), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure until the remaining volume not yet reached 500 ml. The resulting material was filtered and washed with ethyl acetate (800 mL). The product was dried at 45 ° C in a vacuum oven overnight. The product was triturated with water (2.1 L) for 4.5 hours at 50 ° C, then filtered and dried at 45 ° C in a vacuum oven overnight to give 2 - ((1R, 4R) -4- hydroxycyclohexylamino) -4- (isopropylamino) pyrimidine-5-carboxamide (134 g, 70% yield);¹H-NMR (499 MHz, DMSO-d₆) Δ hr. / Million 8,71-9,01 (m, 1H), 8.33 (br. S., 1H), 7,42-7,70 (m, 1H), 6,67-7, 12 (m, 2H), 4.51 (d, J = 3,94 Hz, 1H), 3,98-4,25 (m, 1H), 3,51-3,77 (m, 1H), 3 , 34-3,41 (m, 1H), 1.82 (br. s., 4H), 1,06-1,33 (m, 10H). MS (ESI) m / z 294,1 [M + 1]⁺.

Example 36: (1R, 4R) -4- (5-cyano-4 - ((1R, 3S) -3-gidroksi-3-metiltsiklogeksilamino) pyrimidin-2-ylamino) -N, N-dimetiltsiklogeksankarboksamid

<img file="00000142.jpg" he="41" wi="64" img-format="tif" img-content="undefined" />

A. tert-butyl (1R, 4R) -4- (dimethylcarbamoyl) cyclohexylcarbamate. A mixture of (1R, 4R) -4- (tert-butoxycarbonylamino) cyclohexanecarboxylic acid (7.5 g, 30.8 mmol), EDC (20,09 g, 105 mmol), HOBt (16,05 g, 105 mmol) in NMP (60 ml) was stirred at room temperature for 2 hours. a solution of dimethylamine (46.2 ml, 92 mmol) (2.0 M in THF) and the reaction mixture was stirred for 2 days. Water and ethyl acetate were added and the phases separated. The organic phase was washed twice with saturated aqueous potassium carbonate solution and then with 1M aqueous hydrogen chloride and saturated brine. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated to give the desired product (5.8 g, 19.3 mmol, 96% yield). MS (ESI) m / z 271,4 [M + 1]⁺.

B. Гидрохлорид (1R,4R)-4-амино-N,N-диметилциклогексанкарбоксамида. Трет-бутил-(1R,4R)-4-(диметилкарбамоил)циклогексилкарбамат (8,27 г, 30,6 ммоль) растворяли в диоксане (110 мл) и добавляли хлористоводородную кислоту (38,5 мл, 1267 ммоль). Реакционную смесь перемешивали при комнатной температуре в течение 4 ч, добавляли толуол, и растворитель упаривали с получением продукта (6,0 г, 29,0 ммоль, 95% выход). ¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8.22 (br. S., 3H), 3.01 (s, 3H), 2.86-2.98 (m, 1H), 2.79 (s, 3H), 1 , 93-2,04 (m, 2H), 1.72 (d, J = 7,81 Hz, 2H), 1.31-1.48 (m, 4H). MS (ESI) m / z 171,4 [M + 1]^+.

C. (1R, 4R) -4- (5-Bromo-4- (methylthio) pyrimidin-2-ylamino) -N, N-dimetiltsiklogeksankarboksamid. To a stirred suspension of 5-bromo-2-chloro-4- (methylthio) pyrimidine (1.5 g, 6.26 mmol) in ethanol (7.5 mL) was added hydrochloride (1R, 4R) -4-amino-N, N-dimetiltsiklogeksankarboksamida (1.618 g, 7.83 mmol) and DIEA (3.28 mL, 18.79 mmol). The resulting mixture was stirred at 80 ° C overnight. Ethanol was removed under reduced pressure and the residual solid was purified using chromatography on silica gel (0-90% ethyl acetate in hexane) to give (1R, 4R) -4- (5-bromo-4- (methylthio) pyrimidin-2-ylamino) -N, N-dimetiltsiklogeksankarboksamida (1085 mg, 2.91 mmol, 46.4% yield). MS (ESI) m / z 373,0 [M + 1]⁺, 375.2 [M + 1]⁺.

D. (1R, 4R) -4- (5-Cyano-4- (methylthio) pyrimidin-2-ylamino) -N, N-dimetiltsiklogeksankarboksamid. (1R, 4R) -4- (5-Bromo-4- (methylthio) pyrimidin-2-ylamino) -N, N-dimetiltsiklogeksankarboksamid (500 mg, 1,339 mmoly) tsinkovaya pыly (21.90 mg, 0.335 mmoly) cyanide zinc (102 mg, 0.871 mmoly), 1,1'-bis (diphenylphosphino) -ferrotsen (60.0 mg, 0.107 mmoly), tris (dibenzylideneacetone) dipalladiy (0) (61.3 mg, 0.067 mmoly) and N, N-dimethylacetamide (2,178 ml) obaedinyali and poluchennuyu smesy peremeshivali and heated at 90 ° C for nochi. Reaktsionnuyu smesy razbavlyali эtilatsetatom (125 ml) and water (50 ml) and filytrovali cherez pad throughout. Filytrat sloi manure removal, and vodnыy layer эkstragirovali эtilatsetatom (75 ml). Obaedinennыe эtilatsetatnыe sloi promыvali nasыshtennыm solevыm rastvorom (50 ml), dried over bezvodnыm sulyfatom Magna, filtered and concentrated to an oil under reduced pressure. The oil was purified using chromatography on silica gel (0-10% methanol in DCM) to give (1R, 4R) -4- (5-cyano-4- (methylthio) pyrimidin-2-ylamino) -N, N-dimetiltsiklogeksankarboksamid (400mg , 1.252 mmol, 93% yield) as a solid. MS (ESI) m / z 320,2 [M + 1]⁺.

E. (1R, 4R) -4- (5-Cyano-4- (metilsulyfonil) pyrimidin-2-ylamino) -N, N-dimetiltsiklogeksankarboksamid. K rastvoru (1R, 4R) -4- (5-cyano-4- (methylthio) pyrimidin-2-ylamino) -N, N-dimetiltsiklogeksankarboksamida (400 mg, 1.252 mmoly) in NMP (6,261 ml) at 0 ° C dobavlyali mCPBA (702 mg, 3.13 mmoly). Reaktsionnuyu smesy peremeshivali over 1 h at 0 ° C, and at a temperature zatem okruzhayushtey sredы over nochi. Simply entails zatem ispolyzovali adjacent the sleduyushtey stages without dopolnitelynoy purification, the putative teoreticheskiy vыhod (1R, 4R) -4- (5-cyano-4- (metilsulyfonil) pyrimidin-2-ylamino) -N, N-dimetiltsiklogeksankarboksamida (440 mg, 1 25 mmoly, 100% vыhod). MS (ESI) m / z 352,3 [M + 1]⁺.

F. (1R, 4R) -4- (5-Cyano-4 - ((1R, 3S) -3-gidroksi-3-metiltsiklogeksilamino) pyrimidin-2-ylamino) -N, N-dimetiltsiklogeksankarboksamid. K rastvoru (1R, 4R) -4- (5-cyano-4- (metilsulyfonil) pyrimidin-2-ylamino) -N, N-dimetiltsiklogeksankarboksamida (440 mg, 1.252 mmoly) in NMP (6,261 ml) dobavlyali gidrohlorid (1S, 3R) -3-amino-1-metiltsiklogeksanola (259 mg, 1.565 mmoly) and DIЭA (1,312 mL, 7.51 mmoly). Reaktsionnuyu smesy peremeshivali at 80 ° C for 4 h and zatem ostavlyali ohlazhdatysya to temperaturы okruzhayushtey sredы over nochi. Sыruyu reaktsionnuyu smesy kontsentrirovali at ponizhennom davlenii and ochishtali, ispolyzuya polupreparativnuyu VЭZHH with convertibility a phase (5-60% acetonitrile + 0.1% TFU in aqueous, + 0.1% TFU, over 30 min). Fractions soderzhashtie product kontsentrirovali at ponizhennom davlenii. Poluchennoe tverdoe substance eshte diff rastvoryali in methanol (5 ml),¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8.11 (s, 1H), 7.58 (d, J = 7,81 Hz, 2H), 4,70-5,01 (m, 1H), 4,12-4, 42 (m, 2H), 3,52-3,79 (m, 1H), 3.00 (s, 3H), 2.79 (s, 3H), 1,21-2,07 (m, 16H) , 1,03-1,20 (m, 3H). MS (ESI) m / z 401,5 [M + 1]⁺.

Example 37: 2 - ((1R, 4R) -4-Gidroksiciklogeksilamino) -4- (tert-pentylamino) pyrimidine-5-carboxamide

<img file="00000143.jpg" he="33" wi="54" img-format="tif" img-content="undefined" />

A. 2- (Methylthio) -4- (tert-pentylamino) pyrimidine-5-carbonitrile. 4-Chloro-2- (methylthio) pyrimidine-5-carbonitrile (500 mg, 2.69 mmol) was dissolved in DMF (5 mL) was added 2-methylbutane-2-amine (0.378 mL, 3.24 mmol) and DIEA (1.411 mL, 8.08 mmol) and the reaction mixture was heated at 70 ° C overnight. LC-MS showed that the desired product had a mass of the dominant peak and the starting material remained. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed once with saturated brine, and then dried over magnesium sulfate, filtered and condensed. The crude material was purified by silica gel chromatography (0-80% ethyl acetate in hexanes over 1650 mL, 40 mL / min). The product fractions were combined, evaporated and dried under high vacuum to give 2- (methylthio) -4- (tert-pentylamino) pyrimidine-5-carbonitrile (359 mg, 1.519 mmol, 56.4% yield) as a white solid; MS (ESI) m / z 236,9 [M + 1]⁺.

C. 2- (Metilsulьfonil) -4- (tert-pentylamino) pyrimidine-5-carbonitrile. 2- (Methylthio) -4- (tert-pentylamino) pyrimidine-5-carbonitrile (350 mg, 1.481 mmolь) rastvorяli in NMP (5 ml) and cooled to 0 ° C and zatem porciяmi dobavlяli mCPBA (664 mg, 2 96 mmolь). Reakcionnuю smesь podderzhivali at 0 ° C and ostavlяli medlenno nagrevatьsя in komnatnoй temperature. Cherez 2 h CHO-MS showed product celevoй saw dominantnogo peak and otsutstvie ishodnogo product. Sыruю reakcionnuю smesь ispolьzovali in sleduющeй adjacent stages putative teoreticheskiй vыhod sulьfona; MS (ESI) m / z 269,2 [M + 1]⁺.

C. 2 - ((1R, 4R) -4-hydroxycyclohexylamino) -4- (tert-pentylamino) pyrimidine-5-carbonitrile. To the crude reaction mixture from the previous step was added hydrochloride (1R, 4R) -4-aminocyclohexanol (269 mg, 1.775 mmol) and DIEA (1.034 mL, 5.92 mmol). The reaction mixture was then heated at 70 ° C overnight. LCMS showed desired product and the predominant absence of starting material. The reaction mixture was cooled and then partitioned between ethyl acetate and water. The organic layer was washed once with saturated brine, and then dried over magnesium sulfate, filtered and concentration under reduced pressure. The material was purified by semipreparative HPLC (5-80% acetonitrile + 0.1% TFA in water + 0.1% TFA). The product fractions were combined and concentrated under reduced pressure to a volume of &lt;5 mL. The substance is then neutralized with saturated sodium bicarbonate and extracted with ethyl acetate (2x). The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting solid was dissolved in methanol and washed through a pipe with a polymer SPE Varian StratoSpheres PL-HCO3, eluting with methanol. Evaporation of the solvent under reduced pressure gave 2 - ((1R, 4R) -4-hydroxycyclohexylamino) -4- (tert-pentylamino) pyrimidine-5-carbonitrile (200 mg, 0.659 mmol, 45% yield) as a white solid;¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8,07-8,24 (m, 1H), 7,24-7,63 (m, 1H), 5,67-5,95 (m, 1H), 4.56 (d , J = 4,69 Hz, 1H), 3.35-3.60 (m, 2 H), 1.74-1.96 (m, 6H), 1,09-1,43 (m, 10H) , 0,72-0,86 (m, 3H); MS (ESI) m / z 304,1 [M + 1]⁺.

D. 2 - ((1R, 4R) -4-Gidroksiciklogeksilamino) -4- (tert-pentylamino) pyrimidine-5-carboxamide. 2 - ((1R, 4R) -4-Gidroksiciklogeksilamino) -4- (tert-pentylamino) pyrimidine-5-carbonitrile (141 mg, 0.465 mmolь) rastvorяli in DMSO (3 mL) and 10 dobavlяli kapelь vodnogo 50% dissolved sodium gidroksida 10 kapelь vodnogo 30% dissolved hydrogen in perekisni komnatnoй temperature. Reakcionnuю smesь zatem heated at 50 ° C. Cherez 30 min CHO-MS showed product celevoй saw dominantnogo peak and otsutstvie ishodnogo product. Reakcionnuю smesь cooling and medlenno dobavlяli k ~ 50 ml ledяnoй vodы. Poluchennoe substance ostavlяli peremeshivatьsя over 3 h and zatem filьtrovali and sushitь vыsokom in vacuum at 60 ° C nochi. The resulting 2 - ((1R, 4R) -4-gidroksiciklogeksilamino) -4- (tert-pentylamino) pyrimidine-5-carboxamide (125 mg, 0.389 mmolь, vыhod 84%);¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 9.14 (s, 1H), 8.31 (s, 1H), 7.00 (d, J = 7.81 Hz, 1H), 4.53 (d, J = 4, 29 Hz, 1H), 3.38 (d, J = 3,51 Hz, 2H), 1,74-1,92 (m, 6H), 1.36 (s, 7H), 1,13-1, 31 (m, 4H), 0.80 (t, J = 7,42 Hz, 3H); MS (ESI) m / z 322,0 [M + 1]⁺.

Example 38: 4- (bicyclo [1.1.1] pentan-1-ylamino) -2 - ((1R, 4R) -4-gidroksiciklogeksilamino) pyrimidine-5-carboxamide

<img file="00000144.jpg" he="32" wi="52" img-format="tif" img-content="undefined" />

A. Ethyl-4- (bicyclo [1.1.1] pentan-1-ylamino) -2- (methylthio) pyrimidine-5-carboxylate. A mixture of ethyl-4-chloro-2- (methylthio) pyrimidine-5-carboxylate (200 g, 0.86 mol), hydrochloride bicyclo [1.1.1] pentan-1-amine (171 g, 1.11 mol; obtained in accordance with Org. Lett., 13 (17): 4746-4748 (2011)), and DIEA (278 g, 2.15 mol) in ethanol (2.4 l) peremešivali in week komnatnoj overnight at temperature. After the completion of reaction, be dissolved in koncentrirovali ponižennom pressure syrogo with receipt of the product, which razbavlâli water (1 l). Water layer ékstragirovali chloroform (2 × 1 l), and the associated organic layers promyvali nasyŝennym solevym solution and dried over sodium sulfate bezvodnym. Uparivanie Solvent gave celevoe joint (231 g, 0.83 mol, 96% output) in the form of light-brown oils, which was contaminated with trace amounts of DIEA. This product was used in the next reaction without further purification;¹Н-ЯМР (400 МГц, CDCl₃) Δ hr. / Million 8.61 (s, 2H), 4.30 (q, J = 7,2 Hz, 2H), 2.54 (s, 3H), 2.51 (s, 1H) 2 20 (s, 6H), 1.35 (t, J = 7,2 Hz, 3H).

B. 4- (Bicyclo [1.1.1] pentan-1-ylamino) -2- (methylthio) pyrimidine-5-karbonovaâ acid. Ethyl-4- (bicyclo [1.1.1] pentan-1-ylamino) -2- (methylthio) pyrimidine-5-carboxylate (120 g, 0.43 mol) in rastvorâli ethanol (1.5 l), and then dobavlâli Water Sodium gidroksida solution (530 mL, 1.06 mol, 2M), and polučennuû peremešivali blend in a week komnatnoj overnight at temperature. After that paired be dissolved in ponižennom pressure (temperature baths &lt;42 ° C). Mixture razbavlâli 500 ml of water and tert-promyvali butilmetilovym EFIR (2 × 500 ml). Water layer obrabatyvali Aquatic solution hloristovodorodnoj Acid (2N) to pH 4.2-4.5. Solid substances received by gathering place through filtering, and then promyvali water (500 ml) and Hexane (500 ml). Vlažnuû Lepeška ponižennom dried at pressures in the week overnight at 45 ° C, with receipt of celevogo Connection (108 g, 0.43 mol,¹H-NMR (400 MHz, CD₃OD) δ hr. / Million 8.52 (s, 1H), 2.55 (s, 3H), 2.52 (s, 1H), 2.24 (s, 6H).

S. 4- (Bicyclo [1.1.1] pentan-1-ylamino) -2- (methylthio) pyrimidine-5-carboxamide. To a solution of 4- peremešivaemomu (bicyclo [1.1.1] pentan-1-ylamino) -2- (methylthio) pyrimidine-5-karbonovoj acids (108 g, 0.43 mol) and HOBt (67 g, 0.49 mol) in anhydrous TGF (4 l) under a caplet dobavlâli blend of EDC (94 g, 0.49 mol) in acetonitrile (2 l) at komnatnoj temperature. Thereafter reakcionnuû blend peremešivali in week 1 h at komnatnoj temperature, a caplet dobavlâli Water gidroksid ammonia (600 ml, 28-30% koncentrirovali, 10 eq.) For 30 min, and then mix nagrevali akkuratnogo to boiling with a refrigerator in inverse Within 3 h (60 ± 5 ° C). After that all be dissolved in udalâli ponižennom pressure, pasta ostavšuûsâ / tverdoe substance razbavlâli nasyŝennym Aquatic sodium bicarbonate solution (2 l), and the suspension polučennuû filʹtrovali celevogo with receipt of connection (100 g, 0.4 mol, 93% yield) as an off-white fluffy solid; MC (ESI): m / z 251,1 [M + 1]⁺.

D. 4- (Bicyclo [1.1.1] pentan-1-ylamino) -2- (methylsulfinyl) pyrimidine-5-carboxamide. To a solution of 4- peremešivaemomu (bicyclo [1.1.1] pentan-1-ylamino) -2- (methylthio) pyrimidine-5-carboxamide (76 g, 0.304 mol) in chloroform (7 l) dobavlâli 3-phenyl-2- ( phenylsulfonyl) -1,2-oxaziridine (143 g, 0.547 mol, 1.8 eq.), and recieved light yellow solution peremešivali at Ambient temperature in within a night. Reakcionnyj solution koncentrirovali in ponižennom pressure syrogo with receipt of the product in the form of a rigid white substances, which razbavlâli ethyl acetate (1.5 l), and in vzvesʹ peremešivali komnatnoj temperature in week 1 h. Polučennuû suspension filʹtrovali, promyvali ethyl acetate and dried under vacuum with receipt celevogo connexion (73 g, 0.274 mol, 90% output) in the form of a rigid white substances; MC (ESI): m / z 267.0 [M + 1]⁺.

E. 4- (Bicyclo [1.1.1] pentan-1-ylamino) -2 - ((1R, 4R) -4-gidroksiciklogeksilamino) pyrimidine-5-carboxamide. A mixture of (1R, 4R) -4-aminociklogeksanola (151.4 g, 1.314 mol) and anhydrous DMF (500 ml) nagrevali at ~ 100 ° C. To a mixture of this Porcia dobavlâli 4- (bicyclo [1.1.1] pentan-1-ylamino) -2- (methylsulfinyl) pyrimidine-5-carboxamide (100 g, 0.376 mol) in a nitrogen atmosphere, and reakcionnuû peremešivali blend at 110 ° C in the week nights. Cooling blend Reakcionnuû to ~ 45 ° C, and DMF udalâli ponižennom in pressure with the addition of posleduûŝim water (500 ml) and ethyl acetate (500 ml). Recieved þ vzvesʹ filʹtrovali promyvali and ethyl acetate (50 ml). Tverdoe substance dried at 55 ° C in a vacuum within the next 48 h with receipt syrogo 100 g of product. For removing a quantity of organic sledovyh Solvent crude product suspendirovali in water (1 l) and peremešivali week in 4.5 h, maintaining the internal temperature at 50 ± 1 ° C. The slurry was filtered at 45-50 ° C and washed with water (50 mL). The wet cake was dried in vacuo at 45-50 ° C for 48 hours to give the title compound (92 g, 0.289 mol, 77% yield);¹H-ЯМР (CD₃OD, 400 MHz): δ h / million 8.26 (s, 1H), 3.79 (m, 1H), 3,56-3,58 (m, 1H), 2.47 (s, 1H). , 2.18 (s, 6H), 1.98-2.06 (m, 4H), 1.32-1.39 (m, 4H); MC (ESI): m / z 318,1 [M + 1]⁺.

Example 39: 2 - ((1R, 4R) -4-Gidroksitsiklogeksilamino) -4- (1-metiltsiklopropilamino) pyrimidine-5-carboxamide

<img file="00000145.jpg" he="32" wi="56" img-format="tif" img-content="undefined" />

A. (1R, 4R) -4- (5-Bromo-4- (methylthio) pyrimidin-2-ylamino) -cyclohexanol. 3-liter 3-necked round bottom flask was equipped with a temperature controller J-KEM, mechanical stirrer and nitrogen inlet. The flask was filled with 5-bromo-2-chloro-4- (methylthio) pyrimidine (100 g, 417.5 mmol), (1R, 4R) -4-aminocyclohexanol (76.4 g, 663.4 mmol) and ethanol (1 l). Was added DIEA (109 mL, 626.3 mmol) and the mixture heated at reflux overnight. TLC (1: 1 hexane / ethyl acetate) analysis after 20 h showed complete reaction. The reaction mixture was allowed to cool at room temperature. Water (300 ml) and the precipitate formed gradually. The solid was filtered and washed with water to obtain 111.7 g of a white solid. The filtrate was extracted with ethyl acetate (3 × 300 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to a semisolid. With semisolid form a slurry in 1: 1 hexane / ethyl acetate and filtered to give an additional portion of 12.1 g of a white solid. Two batches were combined to give 123.8 g (93%) (1R, 4R) -4- (5-bromo-4- (methylthio) pyrimidin-2-ylamino) -cyclohexanol as a white solid. MS (ESI) m / z 318, 320 [M + 1]⁺.

B. 2 - ((1R, 4R) -4-hydroxycyclohexylamino) -4- (methylthio) pyrimidine-5-carbonitrile. 2-liter 3-necked round bottom flask was equipped with a temperature controller J-KEM, mechanical stirrer and nitrogen inlet. The flask was filled with a nitrogen atmosphere (1R, 4R) -4- (5-bromo-4- (methylthio) pyrimidin-2-ylamino) cyclohexanol (123.8 g, 389 mmol), zinc cyanide (29.2 g, 249 mmol ), zinc dust (6.36 g, 97 mmol) and N, N-dimethylacetamide (478 ml). Was added tris (dibenzylideneacetone) dipalladium (0) (17.8 g, 0.05 eq.) And 1,1'-bis (diphenylphosphino) ferrocene (17.25 g, 0.08 eq.) And the mixture purged with nitrogen . The reaction mixture was heated to 100 ° C overnight. TLC (2: 1 ethyl acetate / hexane) analysis after 17 h indicated complete reaction. The reaction mixture was allowed to cool at room temperature and diluted with ethyl acetate (2 L). The mixture was filtered through a short pad of Celite, and pad was washed with ethyl acetate (3 × 400 mL). The combined organic layers were washed with water (1 L) and brine (400 mL), dried over sodium sulfate and filtered. The filtrate was concentrated to remove most of the solvent, and the beige precipitate is formed. The solids were filtered and washed with ethyl acetate (2 × 50 mL) to give 55 g (54%) of 2 - ((1R, 4R) -4-hydroxycyclohexylamino) -4- (methylthio) pyrimidine-5-carbonitrile as a beige solid. MS (ESI) m / z 265 [M + 1] The solids were filtered and washed with ethyl acetate (2 × 50 mL) to give 55 g (54%) of 2 - ((1R, 4R) -4-hydroxycyclohexylamino) -4- (methylthio) pyrimidine-5-carbonitrile as a beige solid. MS (ESI) m / z 265 [M + 1] The solids were filtered and washed with ethyl acetate (2 × 50 mL) to give 55 g (54%) of 2 - ((1R, 4R) -4-hydroxycyclohexylamino) -4- (methylthio) pyrimidine-5-carbonitrile as a beige solid. MS (ESI) m / z 265 [M + 1]⁺.

C. 2 - ((1R, 4R) -4-Gidroksiciklogeksilamino) -4- (methylsulfinyl) pyrimidine-5-carbonitrile and 2 - ((1R, 4R) -4-gidroksiciklogeksilamino) -4- (methylsulfonyl) pyrimidin-5- carbonitrile. To peremešannomu bescvetnomu solution of 2 - ((1R, 4R) -4-gidroksiciklogeksilamino) -4- (methylthio) pyrimidine-5-carbonitrile (0, 700 g, 2.65 mmol) in NMP (10 ml) mCPBA dobavlâli (1, 306 g, 5.83 mmol) at 0 ° C. Reakcionnuû blend afterwards in peremešivali komnatnoj temperature in week 2 h before complete reactions, on what pointing ZH-MS. Reakcionnuû mix perenosili the Stadio FOLLOWING no extra cleaning. MS (ESI) m / z 281.4 [M + 1]⁺and 297.2 [M + 1]⁺.

D. 2 - ((1R, 4R) -4-hydroxycyclohexylamino) -4- (1-Methylcyclopropylamine) -pyrimidine-5-carbonitrile. To the reaction mixture of 2 - ((1R, 4R) -4-hydroxycyclohexylamino) -4- (methylsulfinyl) pyrimidine-5-carbonitrile and 2 - ((1R, 4R) -4-hydroxycyclohexylamino) -4- (methylsulfonyl) pyrimidin-5 -carbonitrile from the previous step was added DIEA (2.78 mL, 15.89 mmol) and 1-metiltsiklopropanamina hydrochloride (0.627 g, 5.83 mmol). The reaction mixture was stirred at 90 ° C for 16 hours. After completion of reaction as indicated by LCMS and TLC, the reaction mixture was concentrated and purified by chromatography on silica gel using a gradient of 0% -80% ethyl acetate in hexane. The product fractions were combined and concentrated to give 2 - ((1S, 4S) -4-hydroxycyclohexylamino) -4- (1-Methylcyclopropylamine) -pyrimidine-5-carbonitrile (0.147 g, 19% yield) as a pale yellow solid.⁺.

E. 2 - ((1R, 4R) -4-Gidroksitsiklogeksilamino) -4- (1-metiltsiklopropilamino) pyrimidine-5-carboxamide. 2 - ((1R, 4R) -4-Gidroksitsiklogeksilamino) -4- (1-metiltsiklopropilamino) pyrimidine-5-carbonitrile (0.225 g, 0.783 mmoly) rastvoryali in DMSO (15 mL). In reaktsionnuyu smesy dobavlyali gidroksid sodium (50% mass, 175 .mu.l, 0.783 mmoly) and 30% hydrogen perekisy (175 .mu.L, 1,543 mmoly) at komnatnoy temperature. Reaktsionnuyu smesy peremeshivali at 50 ° C for 1 h. Then and payable reactions of Chto ukazыvala CHO-MS and TLC reaktsionnuyu smesy cooled at komnatnoy temperature and vыlivali in 300 ml ledyanoy vodы. Vodnыy layer эkstragirovali 20% izopropanolom in the chloroform (× 3), and obaedinennыe organicheskie sloi dried over bezvodnыm sulyfatom Magna and kontsentrirovali. Sыruyu smesy ochishtali hromatografiey with convertibility a phase of silica, ispolyzuya gradient 0% -90% methanol in presenter.¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 9.10 (s, 1H), 8.33 (s, 1H), 7.06 (d, J = 7.42 Hz, 1H), 4.53 (d, J = 4, 30 Hz, 1H), 3.59-3.70 (m, 1H), 3.35-3.46 (m, 1H), 1.96 (d, J = 9,76 Hz, 1H), 1, 85 (d, J = 9,76 Hz, 2H), 1.40 (s, 3H), 1.20-1.34 (m, 4H), 0,81-0,89 (m, 1H), 0 , 58-0,71 (m, 4H); MS (ESI) m / z 306,4 [M + 1]⁺.

Example 40: 4 - ((R) -1-cyclopropylethylamino) -2 - ((1R, 4R) -4-gidroksiciklogeksilamino) pyrimidine-5-carboxamide

<img file="00000146.jpg" he="32" wi="56" img-format="tif" img-content="undefined" />

A. 2 - ((1R, 4R) -4-hydroxycyclohexylamino) -4- (methylthio) pyrimidine-5-carboxamide. 2-liter 3-necked round bottom flask was equipped with a temperature controller J-KEM, mechanical stirrer and nitrogen inlet. The flask was filled with 2 - ((1R, 4R) -4-hydroxycyclohexylamino) -4- (methylthio) pyrimidine-5-carbonitrile (54 g, 204.3 mmol; synthesis described herein) and DMSO (270 mL) and the solution cooled to 0 ° C. To the reaction mixture was slowly added sodium hydroxide (170 ml, 1021 mmol, 6 M in water) and a solution of hydrogen peroxide (99 mL, 1021 mmol, 35% in water). There was an exothermic reaction to 30 ° C. The reaction mixture was heated to 50 ° C for 15 min. TLC (10% methanol / ethyl acetate) analysis indicated the reaction was complete. The mixture was cooled to 10 ° C, diluted with water (800 ml) and stirred for 10 min. The mixture was filtered to give 18 g of crude solid. To recover more product, the filtrate was extracted with ethyl acetate (18 × 250 ml). The combined organic layers were washed with brine (75 mL), dried over sodium sulfate, filtered and concentrated to give 33 g of crude solid. The crude solid were combined and purified on silica gel, eluting with 0-15% methanol / ethyl acetate to give 26 g of off-white solid. Slurry formed a solid in acetonitrile and filtered to give 19.5 g (33%) of 2 - ((1R, 4R) -4-hydroxycyclohexylamino) -4- (methylthio) pyrimidine-5-carboxamide as an off-white solid; MS (ESI) m / z 283,3 [M + 1] The combined organic layers were washed with brine (75 mL), dried over sodium sulfate, filtered and concentrated to give 33 g of crude solid. The crude solid were combined and purified on silica gel, eluting with 0-15% methanol / ethyl acetate to give 26 g of off-white solid. Slurry formed a solid in acetonitrile and filtered to give 19.5 g (33%) of 2 - ((1R, 4R) -4-hydroxycyclohexylamino) -4- (methylthio) pyrimidine-5-carboxamide as an off-white solid; MS (ESI) m / z 283,3 [M + 1] The combined organic layers were washed with brine (75 mL), dried over sodium sulfate, filtered and concentrated to give 33 g of crude solid. The crude solid were combined and purified on silica gel, eluting with 0-15% methanol / ethyl acetate to give 26 g of off-white solid. Slurry formed a solid in acetonitrile and filtered to give 19.5 g (33%) of 2 - ((1R, 4R) -4-hydroxycyclohexylamino) -4- (methylthio) pyrimidine-5-carboxamide as an off-white solid; MS (ESI) m / z 283,3 [M + 1] eluting with 0-15% methanol / ethyl acetate to give 26 g of off-white solid. Slurry formed a solid in acetonitrile and filtered to give 19.5 g (33%) of 2 - ((1R, 4R) -4-hydroxycyclohexylamino) -4- (methylthio) pyrimidine-5-carboxamide as an off-white solid; MS (ESI) m / z 283,3 [M + 1] eluting with 0-15% methanol / ethyl acetate to give 26 g of off-white solid. Slurry formed a solid in acetonitrile and filtered to give 19.5 g (33%) of 2 - ((1R, 4R) -4-hydroxycyclohexylamino) -4- (methylthio) pyrimidine-5-carboxamide as an off-white solid; MS (ESI) m / z 283,3 [M + 1]⁺.

B. 2 - ((1R, 4R) -4-Gidroksiciklogeksilamino) -4- (methylsulfinyl) pyrimidine-5-carboxamide and 2 - ((1R, 4R) -4-gidroksiciklogeksilamino) -4- (methylsulfonyl) pyrimidin-5- carboxamide. To peremešivaemomu želtomu solution of 2 - ((1R, 4R) -4-gidroksiciklogeksilamino) -4- (methylthio) pyrimidine-5-carboxamide (0.400 g, 1.42 mmol) in NMP (5 ml) dobavlâli mCPBA (0.635 g, 2 , 83 mmol) at 0 ° C. Reakcionnuû blend then peremešivali komnatnoj at a temperature in within a 1.5 h before complete reactions, on what pointing ZH-MS. Reakcionnuû mix perenosili the Stadio FOLLOWING no extra cleaning. MS (ESI) m / z 298.0 [M + 1]⁺ and 315.1 [M + 1]⁺.

C. 4 - ((R) -1--cyclopropyl) -2 - ((1R, 4R) -4-hydroxycyclohexylamino) pyrimidine-5-carboxamide. To the reaction mixture of 2 - ((1R, 4R) -4-hydroxycyclohexylamino) -4- (methylsulfinyl) pyrimidine-5-carboxamide and 2 - ((1R, 4R) -4-hydroxycyclohexylamino) -4- (methylsulfonyl) pyrimidin-5 carboxamide from the previous reaction was added DIEA (1.56 mL, 8.95 mmol) and (R) -1-tsiklopropiletanamin (0.254 g, 2.98 mmol). The reaction mixture was stirred at 90 ° C for 16 hours. After completion of reaction as indicated by LCMS and TLC, the reaction mixture was concentrated and purified by reverse phase silica gel using a gradient of 0% -90% methanol in water. The desired fraction was purified again by chromatography on silica gel using a gradient of 0% -15% methanol saturated with ammonia in DCM, and then by semipreparative reversed phase HPLC (0-50% acetonitrile + 0 1% TFA in water + 0.1% TFA, over 30 min). Fractions containing product were concentrated under reduced pressure. The resulting solid was again dissolved in methanol (5 ml) was passed through a SPE tube with a polymer Varian StratoSpheres HCO3- to remove TFA (0.9 mM bicarbonate equivalent per tube) and then concentrated under reduced pressure to give 4 - ((R) -1 -cyclopropyl) -2 - ((1R, 4R) -4-hydroxycyclohexylamino) pyrimidine-5-carboxamide (0.104 g, 22% yield);¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8,87-9,10 (m, 1H), 8.32 (br. S., 1H), 6,68-7,02 (m, 1H), 4.51 (d, J = 3,94 Hz, 1H), 3.52-3.72 (m, 2H), 3.36 (br. s., 1H), 1.82 (br. s., 4H), 1.12 -1.32 (m, 8H), 0.95 (d, J = 6,89 Hz, 1H), 0.25-0.50 (m, 3H), 0,10-0,23 (m, 1H ); MS (ESI) m / z 320,1 [M + 1]⁺.

Example 41: 4 - ((1R, 3R, 4R) -3-Gidroksi-4-metiltsiklogeksilamino) -2- (1-metiltsiklopropilamino) pyrimidine-5-carboxamide

<img file="00000147.jpg" he="41" wi="46" img-format="tif" img-content="undefined" />

A. 5-Bromo-N- (1-methylcyclopropyl) -4- (methylthio) pyrimidin-2-amine. To a stirred suspension of 5-bromo-2-chloro-4- (methylthio) pyrimidine (1.0 g, 4.18 mmol) in ethanol (6.0 ml) was added 1-metiltsiklopropanamin hydrochloride (0.674 g, 6.26 mmol) and DIEA (2.188 mL, 12.53 mmol). The mixture was stirred at 90 ° C for 16 hours. After completion of reaction as indicated by LCMS and TLC, the reaction mixture was concentrated and purified by chromatography on silica gel using a gradient of 0% -20% ethyl acetate in hexane. The product fractions were combined and concentrated to give 5-bromo-N- (1-methylcyclopropyl) -4- (methylthio) pyrimidin-2-amine (0.665 g, 58% yield) as a white solid. MS (ESI) m / z 276,2 [M + 1]⁺.

B. 2- (1-Metiltsiklopropilamino) -4- (methylthio) pyrimidine-5-carbonitrile. Chernuyu suspenziyu 5-bromo-N- (1-methylcyclopropyl) -4- (methylthio) pyrimidin-2-amine (0.665 g, 2.425 mmoly), zinc (0.040 g, 0.606 mmoly) cyanide zinc (0.185 g, 1,577 mmoly) , 1,1'-bis (diphenylphosphino) ferrotsena (0.109 g, 0.194 mmoly), tris (dibenzylideneacetone) dipalladiya (0) (0.111 g, 0.121 mmoly) and N, N'-dimethylacetamide (6 mL) and heated promыvali azotom at 90 ° C for 16 h. Then and payable reactions of Chto ukazыvala CHO-MS and TLC reaktsionnuyu smesy razbavlyali 125 ml and 50 ml эtilatsetat vodы and filytrovali cherez pad throughout. Sloi filytrata manure removal, and vodnыy layer эkstragirovali 75 ml эtilatsetata. Obaedinennыe эtilatsetatnыe sloi promыvali 2 × 50 ml nasыshtennыm solevыm rastvorom, dried over bezvodnыm sulyfatom Magna, filytrovali and kontsentrirovali to oils. The crude oil was purified by chromatography on silica gel using a gradient of 0% -30% ethyl acetate in hexane. The product fractions were combined and concentrated to give 2- (1-Methylcyclopropylamine) -4- (methylthio) pyrimidine-5-carbonitrile (0.449 g, 84% yield) as a pale yellow solid. MS (ESI) m / z 221,2 [M + 1]⁺.

C. 2- (1-Metiltsiklopropilamino) -4- (metilsulyfonil) pyrimidine-5-carbonitrile. K peremeshannomu bestsvetnomu rastvoru 2- (1-metiltsiklopropilamino) -4- (methylthio) -pyrimidine-5-carbonitrile (0.449 g, 2.04 mmoly) in NMP (6 mL) dobavlyali mCPBA (1,142 g, 5.10 mmoly) at 0 ° C. Reaktsionnuyu smesy zatem peremeshivali at komnatnoy temperature for 1 hour to and payable reactions of Chto ukazыvala CHO-MS. Reaktsionnuyu smesy perenosili in sleduyushtuyu stadiyu dopolnitelynoy without purification. MS (ESI) m / z 253,3 [M + 1]⁺.

D. 4 - ((3R, 4R) -3-Gidroksi-4-metiltsiklogeksilamino) -2- (1-metiltsiklopropilamino) pyrimidine-5-carbonitrile. K reactionary mixtures of 2- (1-metiltsiklopropilamino) -4- (metilsulyfonil) pyrimidine-5-carbonitrile around predыdushtey stages dobavlyali DIЭA (2.14 mL, 12.22 mmoly) and gidrohlorid (1R, 2R, 5R) -5-amino -2-metiltsiklogeksanola (0.371 g, 2,241 mmoly; synthesis described in the present activities as described). Reaktsionnuyu smesy peremeshivali at 90 ° C for 16 h. Then and payable reactions of Chto ukazыvala CHO-MS and TLC reaktsionnuyu smesy kontsentrirovali and ochishtali with pomoshtyyu chromatographies on silica gel, ispolyzuya gradient 0% -60% эtilatsetata in Gexto. Fractions product obaedinyali and kontsentrirovali with polucheniem 4 - ((3R, 4R) -3-gidroksi-4-metiltsiklogeksilamino) -2- (1-metiltsiklopropilamino) pyrimidine-5-carbonitrile (0.185 g, 30% vыhod) in saw light zheltogo tverdogo substances. MS (ESI) m / z 302,1 [M + 1]⁺.

E. 4 - ((1R, 3R, 4R) -3-Gidroksi-4-metiltsiklogeksilamino) -2- (1-metiltsiklopropilamino) pyrimidine-5-carboxamide. 4 - ((3R, 4R) -3-Gidroksi-4-metiltsiklogeksilamino) -2- (1-metiltsiklopropilamino) pyrimidine-5-carbonitrile (0.181 g, 0.601 mmoly) rastvoryali in DMSO (6 mL). Dobavlyali desyaty kapely 50% vodnogo simply entails gidroksida sodium (0.047 ml, 0,901 mmoly) and desyaty kapely 30% vodnogo simply entails perekisni hydrogens on komnatnoy temperature. Reaktsionnuyu smesy peremeshivali at 50 ° C for 1 h. Then and payable reactions of Chto ukazыvala CHO-MS and TLC reaktsionnuyu smesy cooled at komnatnoy temperature and vыlivali in 300 ml ledyanoy vodы. Vodnыy layer эkstragirovali 20% iPrOH / chloroform (× 3), and obaedinennыe organicheskie sloi dried over bezvodnыm sulyfatom Magna and kontsentrirovali. Sыruyu smesy ochishtali with pomoshtyyu polupreparativnoy VЭZHH with convertibility a phase (0-50% acetonitrile + 0 1% TFA in water + 0.1% TFA, over 30 min). Fractions containing product were concentrated under reduced pressure. The resulting solid was again dissolved in methanol (5 ml) was passed through a SPE tube with a polymer Varian StratoSpheres HCO3- to remove TFA (0.9 mM bicarbonate equivalent per tube) and then concentrated under reduced pressure to give 4 - ((1R, 3R, 4R) -3-hydroxy-4-methylcyclohexylamine) -2- (1-Methylcyclopropylamine) pyrimidine-5-carboxamide (0.069 g, 36% yield);¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8,79-8,92 (m, 1H), 8,28-8,39 (m, 1H), 7.32-7.48 (m, 1H), 4.56 (s , 1H), 3,83-3,97 (m, 1H), 2,89-3,08 (m, 1H), 2.18-2.31 (m, 1H), 1.97-2.08 (m, 1H), 1.61-1.74 (m, 1H), 1.35 (s, 4H), 1,05-1,26 (m, 1H), 0.94 (d, J = 6 , 64 Hz, 5H), 0.66 (s, 3H), 0.54 (br s, 3H)..; MS (ESI) m / z 320,2 [M + 1]⁺.

Example 42: 4- (tert-butylamino) -2 - ((1R, 4R) -4-ciklopropoksiciklogeksilamino) pyrimidine-5-carboxamide

<img file="00000148.jpg" he="30" wi="60" img-format="tif" img-content="undefined" />

A. 2 - ((1R, 4R) -4-hydroxycyclohexyl) isoindoline-1,3-dione. To a stirred solution isobenzofuran-1,3-dione (90 g, 0.6 mol) and (1R, 4R) -4-aminocyclohexanol (70 g, 0.6 mol) in toluene (250 ml) and DMF (250 ml) It was stirred at 130 ° C overnight. The reaction mixture was cooled to room temperature, water was added and the product was filtered, washed with water and dried in vacuo to give the title product as a white solid which was used in the next step without further purification (119 g, 0.48 mol, yield: 81 %).¹Н-ЯМР (400 МГц, CDCl₃) Δ hr. / Million 7,84-7,79 (m, 2H), 7.72-7.68 (m, 2H), 4,18-4,10 (m, 1H), 3,80-3 73 (m, 1H), 2,40-2,29 (qd, J1 = 3,4 Hz, J2 = 130 Hz, 2H), 2,12-2,09 (dd, J = 6,2 Hz, 2H), 1.78-1.74 (dd, J = 6,6 Hz, 2H), 1,49-1,39 (qd, J1 = 3,3 Hz, J2 = 125 Hz, 2H).

B. 2 - ((1R, 4R) -4- (vinyloxy) cyclohexyl) isoindoline-1,3-dione. Palladium acetate (11 g, 0.048 mol) in etoksietene (500 ml) was stirred at 0 ° C for 15 min and then a solution of 2 - ((1R, 4R) -4-hydroxycyclohexyl) isoindoline-1,3-dione ( 118 g, 0.48 mol) in etoksietane (1000 ml). The mixture was stirred at 60 ° C for 3 days. The mixture was then cooled to room temperature, filtered and washed with ethyl acetate. The resulting filtrate was concentrated to give a crude product which was purified by chromatography on a silica gel (16.7% -25% ethyl acetate in petroleum ether) to give the compound of the title as a white solid (80 g, 0.29 mol , yield: 61%).¹Н-ЯМР (400 МГц, CDCl₃) Δ hr. / Million 7.84-7.80 (m, 2H), 7.72-7.68 (m, 1H), 6,37-6,32 (dd, J = 6,4 Hz, 1H ), 4,34-4,30 (dd, J = 1,2 Hz, 1H), 4,20-4,12 (m, 1H), 4,04-4,02 (dd, J = 2,0 Hz, 1H), 3,89-3,81 (m, 1H), 2,40-2,29 (qd, J1 = 3,4 Hz, J2 = 130,6 Hz, 2H), 2,21-2 17 (dd, J = 64 Hz, 2H), 1,82-1,78 (dd, J = 64 Hz, 2H), 1,53-1,43 (qd, J1 = 33Hz, J2 = 126 6 Hz, 2H).

C. 2 - ((1R, 4R) -4-Tsiklopropoksitsiklogeksil) isoindoline-1,3-dione. To a stirred mixture of diethyl ether (100 ml) and potassium hydroxide (2.5N, 50 mL) was added 1-nitrosourea (38 g, 0.37 mol) at 0 ° C. After 15 minutes, the ether phase was collected and carefully added to a mixture of 2 - ((1R, 4R) -4- (vinyloxy) cyclohexyl) isoindoline-1,3-dione (10 g, 36.9 mmol) and palladium acetate (826 mg, 3.69 mmol) in diethyl ether (100 ml) and DCM (100 mL). The resulting solution was stirred at 0 ° C for 0.5 hours. The reduction procedure and adding ethereal solution of diazomethane was then repeated three times. After the reaction was completed, the solid in the reaction mixture was filtered, the filtrate was collected and concentrated to give the crude product which was purified by chromatography on a silica gel column (25% ethyl acetate in petroleum ether,¹Н-ЯМР (400 МГц, CDCl₃) Δ hr. / Million 7,84-7,79 (m, 2H), 7.72-7.67 (m, 1H), 4,18-4,09 (m, 1H), 3,56-3 48 (m, 1H), 3,37-3,33 (m, 1H), 2,38-2,27 (qd, J1 = 3, 6 Hz, J2 = 130,6 Hz, 2H), 2, 21-2,18 (dd, J = 6,4 Hz, 1H), 1,79-1,76 (dd, J = 6,4 Hz, 2H), 1,50-1,33 (qd, J1 = 35 Hz, J2 = 126 Hz, 2H), 0,60-0,56 (m, 2H), 0,50-0,46 (m, 2H).

D. (1R, 4R) -4-Tsiklopropoksitsiklogeksanamin. A mixture of 2 - ((1R, 4R) -4-tsiklopropoksitsiklogeksil) isoindoline-1,3-dione (30 g, 0.10 mol) and hydrazine hydrate (18.9 g, 0.31 mol) in methanol (600 ml) was heated at 80 ° C for 2 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was collected and concentrated to give the crude product which was purified by chromatography on a silica gel column (3.33% methanol in DCM) to give (1R, 4R) -4-tsiklopropoksitsiklogeksanamina as a yellow oil (10 g, 64.5 mmol , yield: 61%).¹Н-ЯМР (400 МГц, CDCl₃) Δ hr. / Million 3,40-3,28 (m, 2H), 2,72-2,65 (m, 1H), 2,06-2,03 (dd, J = 3,8 Hz, 2H ), 1,88-1,85 (dd, J = 6,2 Hz, 2H), 1,34-1,24 (qd, J1 = 28 Hz, J2 = 123,3 Hz, 2H), 1.19 -1.09 (qd, J1 = 28 Hz, J2 = 123,3 Hz, 2H), 0,56-0,51 (m, 2H), 0,49-0,44 (m, 2H); MC (ESI) m / z = 156,1 [M + 1]⁺.

E. 4- (tert-butylamino) -2- (metilsulьfonil) pyrimidine-5-carboxamide. K peremeshannomu solvent 4- (tert-butylamino) -2- (methylthio) pyrimidine-5-carboxamide (0.500 g, 2.081 mmolь; synthesis described in the present description) in NMP (6 ml) dobavlяli mCPBA (0,933 g, 4.16 mmolь ) at 0 ° C. Reakcionnuю smesь peremeshivali in komnatnoй temperature for 1 h and payable to the effects of Chto ukazыvala CHO-MS. Reakcionnuю smesь perenosili in sleduющuю stadiю dopolnitelьnoй without purification. MS (ESI) m / z 273,2 [M + 1]⁺.

F. 4- (tert-butylamino) -2 - ((1R, 4R) -4-ciklopropoksiciklogeksilamino) pyrimidine-5-carboxamide. K reactionary mixtures 4- (tert-butylamino) -2- (metilsulьfonil) pyrimidine-5-carboxamide from predыduщeй stages dobavlяli DIЭA (1.5 ml, 8.33 mmolь) and (1R, 4R) -4-ciklopropoksiciklogeksanamin (0.485 g, 3.12 mmolь). Reakcionnuю smesь peremeshivali at 90 ° C for 16 h. After due and payable reactions, as it seems to ukazыvala CHO-MS and TLC reakcionnuю smesь medlenno dobavlяli k ~ 70 ml ledяnoй vodы. Эtot product filьtrovali, promыvali water and zatem minimalьnыm amount эtanola and diэtilovogo эfira and dried zatem polucheniem soedineniя, ukazannogo in zagolovke, 4- (tert-butylamino) -2 - ((1R, 4R) -4-ciklopropoksiciklogeksilamino) -pyrimidin -5-carboxamide (0.214 g, 30% vыhod);¹H-NMR (400 MHz, DMSO-d₆) Δ 9,18 (s, 1H), 8.32 (s, 1H), 7.02-7.08 (m, 1H), 3,57-3,67 (m, 1H), 3.30 ( t, J = 2,93 Hz, 1H), 1.99-2.09 (m, 2H), 1.85-1.94 (m, 2H), 1.41 (s, 11H), 1.28 (. br s, 5H.), 0,37-0,46 (m, 4H); MS (ESI) m / z 348,3 [M + 1]⁺.

Example 43: 4 - ((1R, 3S) -3-hydroxycyclohexylamino) -2 - ((1R, 4R) -4-hydroxycyclohexylamino) pyrimidine-5-carbonitrile

<img file="00000149.jpg" he="34" wi="56" img-format="tif" img-content="undefined" />

A. 4 - ((1R, 3S) -3-hydroxycyclohexylamino) -2 - ((1R, 4R) -4-hydroxycyclohexylamino) pyrimidine-5-carbonitrile. 2-Chloro-4 - ((1R, 3S) -3-hydroxycyclohexylamino) pyrimidine-5-carbonitrile (240 mg, 0.950 mmol; synthesis described herein), hydrochloride (1R, 4R) -4-aminocyclohexanol (216 mg, 1.425 mmol) and cesium carbonate (619 mg, 1.899 mmol) was suspended in 1,4-dioxane (10 ml) and heated at 80 ° C for 3 hrs. LCMS indicated that the desired product had a mass peak and dominant source product missing. The reaction mixture was concentrated and purified by chromatography on a silica gel column (10-100% ethyl acetate in hexane, then 0-15% methanol in DCM) to afford compound the title compound (159 mg, 0 480 mmol, 50.5% exit);¹Н-ЯМР (ie ДМСО₆, 400 MHz) δ hr. / Million 8,06-8,24 (m, 1H), 7,09-7,57 (m, 2H), 4.74 (d, J = 4,3 Hz, 1H) , 4,48-4,63 (m, 1H), 3,89-4,16 (m, 1H), 3,34-3,74 (m, 3H), 1,53-2,09 (m, 8H), 0,99-1,51 h / million (m, 8H).; MS (ESI) m / z 332,1 [M + 1]⁺.

Example 44: 4 - ((1R, 3S) -3-Gidroksitsiklogeksilamino) -2 - ((1R, 4R) -4- (2,2,2-triftorэtoksi) tsiklogeksilamino) pyrimidine-5-carbonitrile

<img file="00000150.jpg" he="40" wi="69" img-format="tif" img-content="undefined" />

A. 4 - ((1R, 3S) -3-hydroxycyclohexylamino) -2 - ((1R, 4R) -4- (2,2,2-trifluoroethoxy) cyclohexylamino) pyrimidine-5-carbonitrile. To a stirred solution of 2-chloro-4 - ((1R, 3S) -3-hydroxycyclohexylamino) pyrimidine-5-carbonitrile (113 mg, 0.447 mmol; synthesis described herein) and (1R, 4R) -4- (2, 2,2-trifluoroethoxy) cyclohexanamine (150 mg, 0.761 mmol; synthesis described herein) in DMSO (6.0 mL) was added DIEA (0.156 mL, 0.895 mmol). The resulting mixture was stirred at ambient temperature for 3 days. DMSO was removed under reduced pressure and the residual solid was purified using chromatography on silica gel (0-40% ethyl acetate + 10% 7N ammonia in methanol in hexanes) to give compound the title compound (156 mg, 0.378 mmol, 84.6% exit).¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8,03-8,29 (m, 1H), 7,10-7,62 (m, 2H), 4.74 (d, J = 3,90 Hz, 1H), 4, 05 (q, J = 9,37 Hz, 3H), 3,36-3,82 (m, 3H), 1,55-2,13 (m, 8H), 1.00-1.50 (m, 8H). ¹⁹F ЯМР (376 МГц, ДМСО-d₆) Δ hr. / Million -73.64 (t, J = 9,19 Hz, 3F). MS (ESI) m / z 414,2 [M + 1]⁺.

Example 45: 2 - ((1R, 4R) -4- (Diftormetoksi) tsiklogeksilamino) -4 - ((1R, 3S) -3-gidroksitsiklogeksilamino) pyrimidine-5-carbonitrile

<img file="00000151.jpg" he="33" wi="62" img-format="tif" img-content="undefined" />

A. 2 - ((1R, 4R) -4- (difluoromethoxy) cyclohexylamino) -4 - ((1R, 3S) -3-hydroxycyclohexylamino) pyrimidine-5-carbonitrile. To a stirred solution of 2-chloro-4 - ((1R, 3S) -3-hydroxycyclohexylamino) pyrimidine-5-carbonitrile (100 mg, 0.396 mmol; synthesis described herein) and (1R, 4R) -4- (difluoromethoxy) cyclohexanamine (131 mg, 0.791 mmol; synthesis described herein) in DMSO (4.0 mL) was added DIEA (0.138 mL, 0.791 mmol). The resulting mixture was stirred at ambient temperature overnight. DMSO was removed under reduced pressure and the residual solid was purified using chromatography on silica gel (5-40% ethyl acetate + 10% methanol saturated with ammonia in hexane) to afford compound the title compound (130 mg, 0.340 mmol, 86.0% exit).¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8,08-8,25 (m, 1H), 7,12-7,62 (m, 2H), 6,47-6,94 (m, 1H), 4.74 (d , J = 4,29 Hz, 1H), 3,88-4,18 (m, 2H), 3,41-3,85 (m, 2H), 1,01-2,11 (m, 16H). ¹⁹F ЯМР (376 МГц, ДМСО-d₆) δ ч./млн -79,21--78,76 (м, 2 F). МС (ESI) m/z 382,3 [М+1]⁺.

Example 46: 4- (tert-butylamino) -2- (4-gidroksibiciklo [2.2.1] heptanes-1-ylamino) pyrimidine-5-carboxamide

<img file="00000152.jpg" he="30" wi="54" img-format="tif" img-content="undefined" />

A. Cyclopentane-1,3-dicarboxylic acid. 22-liter 3-necked round bottom flask was equipped with a temperature controller J-KEM, mechanical stirrer and nitrogen inlet. The flask was filled norbornene (200 g, 2.123 mol), ethyl acetate (1.95 L) and acetonitrile (1.95 L). The reaction mixture was cooled to 5 ° C using a bath of acetone / dry ice. One portion was added ruthenium trichloride (9.69 g, 46.72 mmol) and then slowly added to a suspension of sodium periodate (1.816 kg, 8.707 mol) in water (2.925 L) over 30 min. The reaction slowly became exothermic and it was controlled to maintain the temperature between 10 ° C and 15 ° C. After 90 minutes, the reaction mixture was suddenly thickened to the point where stirring was difficult. and the reaction rapidly became exothermic to 39 ° C (to control the exothermic reaction, the cooling bath was added a large amount of dry ice). The reaction mixture was allowed to cool to 20 ° C, the bath of dry ice / acetone bath was removed and the mixture was stirred at room temperature overnight. The solids were removed by filtration through a pad of celite and the filtrate was concentrated to a solid which was triturated with hexane (2 L), filtered and washed with hexane (2x500 mL) to yield 195 g (58%) cyclopentane-1,3- dicarboxylic acid.¹Н-ЯМР (500 Гц, DMCO-d₆) Δ hr. / Million 12.07 (s, 2H), 2.66-2.73 (m, 2H), 2.06-2.12 (m, 1H), 1,85-1,89 (m , 1H), 1.72-1.85 (m, 4H).

B. dimethyl cyclopentane-1,3-dicarboxylate. 5-liter 3-necked round bottom flask was equipped with a mechanical stirrer, temperature controller, J-KEM and reflux condenser. The flask was filled cyclopentane-1,3-dicarboxylic acid (357 g, 2.262 mol) and methanol (1.75 L). The solution was cooled to 7 ° C using an ice / water bath. Was added dropwise concentrated sulfuric acid (70 ml) for 30 minutes, which gave an exotherm to 12 ° C. The reaction mixture was heated at reflux and stirred for 16 hours, after which TLC analysis (10% methanol / ethyl acetate) indicated that the reaction was complete. The reaction mixture was concentrated, again dissolved in methyl tert-butyl ether and washed with saturated aqueous sodium bicarbonate (2 × 150 mL) and brine (2 × 150 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The resulting clear oil was dissolved in hexane (2 L) and treated with 2N aqueous sodium hydroxide (950 mL) until pH ~ 10. The layers was removed and the aqueous layer was extracted with hexane (4 × 1 L). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give 360 ​​g (100%) dimethylcyclopentane-1,3-dicarboxylate as a clear oil.¹Н-ЯМР (500 Гц, CDCl₃) Δ hr. / Million 3.67 (s, 6H), 2.75-2.83 (m, 2H), 2,20-2,26 (m, 1H), 2.05-2.12 (m , 1H), 1,90-2,0 (m, 4H).

S. dimethylbicyclo [2.2.1] heptane-1,4-dicarboxylate. 22-liter 3-necked round bottom flask was equipped with a temperature controller J-KEM, mechanical stirrer, nitrogen inlet and auxiliary funnel. The flask was flushed with nitrogen, then filled with anhydrous THF (5 L) and diisopropylamine (731 mL, 5.219 mol). The solution was cooled to -20 ° C using dry ice bath / acetone. The stirred mixture was treated slowly with 1.6M n-butyllithium in hexane (3.02 L, 4.833 mol) via cannula over 1 hour while maintaining the temperature between -20 ° C and -27 ° C. The reaction mixture was cooled to -40 ° C and slowly added hexamethylphosphoramide (2.7 L, 16.317 mol) via dropping funnel over 40 min. The reaction mixture was cooled to -73 ° C and dimethylcyclopentane-1,3-dicarboxylate (360 g, 1.933 mol) dissolved in anhydrous THF (2 L), was added slowly through an additional funnel over 2 hours. The reaction mixture was warmed to -10 ° C and stirred at the same temperature for 30 minutes, then cooled to -70 ° C and treated with 1-bromo-2-hloretanom (267 ml, 3.209 mol) via additional funnel over 4 hours. The reaction mixture was allowed to warm slowly at room temperature for 12 h and then quenched with saturated aqueous ammonium chloride solution (2 l) for 90 min. The reaction mixture was diluted with hexane (2 L), the layers are removed, and the aqueous layer was further extracted with hexane (3 × 2 L). The combined organic layers were washed with brine (2 × 1 L), dried over sodium sulfate, filtered and concentrated to a brown oil. The crude product was purified on silica gel (0-10% ethyl acetate / hexane). Fractions containing product We concentrated to near dryness and diluted with hexane. The resulting crystalline solids were filtered and washed with hexane (200 ml) to give the pure product as a clear crystalline solid. Additional portions of product was obtained from the filtrate in a similar manner. All product portions were combined to yield 208 g (51%) dimethylbicyclo [2.2.1] heptane-1,4-dicarboxylate as a clear crystalline solid.¹Н-ЯМР (500 Гц, CDCl₃) Δ hr. / Million 3.68 (s, 6H), 2.03 (d, J = 6.4 Hz, 4H), 1.90 (s, 2H), 1.67 (d, J = 7, 0, 4H).

D. 4- (Methoxycarbonyl) bicyclo [2.2.1] heptane-1-carboxylic acid. A 12 liter 3-proud round bottom flask was equipped with a mechanical stirrer, temperature controller and J-KEM-oic 250 mL addition funnel. The flask was filled dimethylbicyclo [2.2.1] heptane-1,4-dicarboxylate (208 g, 980 mmol) and THF (6.7 L). The resulting solution was cooled to 15 ° C using an ice / water bath. Precipitation of sodium hydroxide (39.2 g, 980 mmol) was dissolved in methanol (400 ml) and slowly added to the stirred solution for 30 min. After completion of the addition a white solid began to precipitate. The reaction mixture was stirred at room temperature for 16 h until TLC analysis (100% ethyl acetate) indicated about 90% conversion. The reaction mixture was concentrated to dryness to yield a slurry in hexane (2 L), filtered and washed with hexane (2 × 400 mL). The resulting sodium carboxylate salt was transferred to a 3-liter 3-necked round bottom flask equipped with a mechanical stirrer, was dissolved in water (1 L) and slowly treated with 2N. aqueous hydrochloric acid (430 ml) at 10 ° C until pH ~ 4. The fatty suspension was diluted with ethyl acetate (1 L) and transferred to a separatory funnel. The layers was removed and the aqueous layer was further extracted with ethyl acetate (2 × 500 mL), washed with saturated brine (200 ml), dried over sodium sulfate and concentrated to give 170 g (87%) of 4- (methoxycarbonyl) bicyclo [2.2.1] heptane-1-carboxylic acid. The fatty suspension was diluted with ethyl acetate (1 L) and transferred to a separatory funnel. The layers was removed and the aqueous layer was further extracted with ethyl acetate (2 × 500 mL), washed with saturated brine (200 ml), dried over sodium sulfate and concentrated to give 170 g (87%) of 4- (methoxycarbonyl) bicyclo [2.2.1] heptane-1-carboxylic acid. The fatty suspension was diluted with ethyl acetate (1 L) and transferred to a separatory funnel. The layers was removed and the aqueous layer was further extracted with ethyl acetate (2 × 500 mL), washed with saturated brine (200 ml), dried over sodium sulfate and concentrated to give 170 g (87%) of 4- (methoxycarbonyl) bicyclo [2.2.1] heptane-1-carboxylic acid.¹H NMR (500 Hz, DMSO-d₆) Δ hr. / Million 12.21 (s, 1H), 3.60 (s, 3H), 1.91 (d, J = 6,7 Hz, 4H), 1.75 (s, 2H), 1 , 56-1,62 (m, 4H).

E. 4- (Benzyloxycarbonylamino) bicyclo [2.2.1] heptane-1-carboxylic acid. 2-liter 3-necked, round bottom flask was equipped with a mechanical stirrer, temperature controller, J-KEM, reflux condenser and nitrogen inlet. The flask was filled with 4- (methoxycarbonyl) bicyclo [2.2.1] heptane-1-carboxylic acid (100 g, 0.504 mol) and anhydrous toluene (500 mL). The flask was cooled to 10 ° C and slowly added DIEA (175 mL, 1.008 mol) over 5 minutes to give a secondary exotherm to 14 ° C. The reaction mixture was slowly added diphenylphosphonyl azide (130 mL, 0.605 mol). The mixture was heated to about 60 ° C as gas evolution began. The reaction mixture was rapidly emit large amounts of gas and exotherm gave at reflux. The reaction mixture was stirred at reflux (110 ° C) for 2 hours, then cooled to 50 ° C and slowly treated with benzyl alcohol (104 mL, 1.008 mol) over 5 min. The reaction mixture was again heated to 110 ° C and stirred for 40 h. The reaction mixture was concentrated to an oil in vacuo, dissolved in ethyl acetate (2 L), washed with saturated brine (500 mL) and a layer of brine was extracted with ethyl acetate (2 × 400 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated to a crude oil which was transferred to a 5-liter 3-necked round bottom flask equipped with a mechanical stirrer, temperature controller, J-KEM and nitrogen inlet. The flask was filled with methanol (2 L). The mixture was cooled to 10 ° C and treated with 2N. sodium hydroxide (500 ml) for 5 minutes to give an exotherm to 16 ° C. The reaction mixture was stirred at 60 ° C for 20 h until TLC analysis (20% methanol / ethyl acetate) indicated complete reaction. The reaction mixture was cooled to room temperature and the methanol was removed in vacuo. Upon cooling, the reaction mixture was acidified using 2N. hydrochloric acid (480 mL) to pH 2-3. The aqueous mixture was extracted with ethyl acetate (2 L then 500 ml). The combined organic layers were washed with brine (400 mL), dried over sodium sulfate, and concentrated to give the crude product as a brown oil. The crude product was purified by silica gel chromatography (20-100% ethyl acetate / hexane) to give 132 g (91%) of 4- (benzyloxycarbonylamino) -bicyclo [2.2.1] heptane-1-carboxylic acid. The reaction mixture was stirred at 60 ° C for 20 h until TLC analysis (20% methanol / ethyl acetate) indicated complete reaction. The reaction mixture was cooled to room temperature and the methanol was removed in vacuo. Upon cooling, the reaction mixture was acidified using 2N. hydrochloric acid (480 mL) to pH 2-3. The aqueous mixture was extracted with ethyl acetate (2 L then 500 ml). The combined organic layers were washed with brine (400 mL), dried over sodium sulfate, and concentrated to give the crude product as a brown oil. The crude product was purified by silica gel chromatography (20-100% ethyl acetate / hexane) to give 132 g (91%) of 4- (benzyloxycarbonylamino) -bicyclo [2.2.1] heptane-1-carboxylic acid. The reaction mixture was stirred at 60 ° C for 20 h until TLC analysis (20% methanol / ethyl acetate) indicated complete reaction. The reaction mixture was cooled to room temperature and the methanol was removed in vacuo. Upon cooling, the reaction mixture was acidified using 2N. hydrochloric acid (480 mL) to pH 2-3. The aqueous mixture was extracted with ethyl acetate (2 L then 500 ml). The combined organic layers were washed with brine (400 mL), dried over sodium sulfate, and concentrated to give the crude product as a brown oil. The crude product was purified by silica gel chromatography (20-100% ethyl acetate / hexane) to give 132 g (91%) of 4- (benzyloxycarbonylamino) -bicyclo [2.2.1] heptane-1-carboxylic acid. When TLC analysis (20% methanol / ethyl acetate) indicated complete reaction. The reaction mixture was cooled to room temperature and the methanol was removed in vacuo. Upon cooling, the reaction mixture was acidified using 2N. hydrochloric acid (480 mL) to pH 2-3. The aqueous mixture was extracted with ethyl acetate (2 L then 500 ml). The combined organic layers were washed with brine (400 mL), dried over sodium sulfate, and concentrated to give the crude product as a brown oil. The crude product was purified by silica gel chromatography (20-100% ethyl acetate / hexane) to give 132 g (91%) of 4- (benzyloxycarbonylamino) -bicyclo [2.2.1] heptane-1-carboxylic acid. When TLC analysis (20% methanol / ethyl acetate) indicated complete reaction. The reaction mixture was cooled to room temperature and the methanol was removed in vacuo. Upon cooling, the reaction mixture was acidified using 2N. hydrochloric acid (480 mL) to pH 2-3. The aqueous mixture was extracted with ethyl acetate (2 L then 500 ml). The combined organic layers were washed with brine (400 mL), dried over sodium sulfate, and concentrated to give the crude product as a brown oil. The crude product was purified by silica gel chromatography (20-100% ethyl acetate / hexane) to give 132 g (91%) of 4- (benzyloxycarbonylamino) -bicyclo [2.2.1] heptane-1-carboxylic acid. hydrochloric acid (480 mL) to pH 2-3. The aqueous mixture was extracted with ethyl acetate (2 L then 500 ml). The combined organic layers were washed with brine (400 mL), dried over sodium sulfate, and concentrated to give the crude product as a brown oil. The crude product was purified by silica gel chromatography (20-100% ethyl acetate / hexane) to give 132 g (91%) of 4- (benzyloxycarbonylamino) -bicyclo [2.2.1] heptane-1-carboxylic acid. hydrochloric acid (480 mL) to pH 2-3. The aqueous mixture was extracted with ethyl acetate (2 L then 500 ml). The combined organic layers were washed with brine (400 mL), dried over sodium sulfate, and concentrated to give the crude product as a brown oil. The crude product was purified by silica gel chromatography (20-100% ethyl acetate / hexane) to give 132 g (91%) of 4- (benzyloxycarbonylamino) -bicyclo [2.2.1] heptane-1-carboxylic acid.¹H-NMR (500 Hz, DMSO-d₆) Δ hr. / Million 12.12 (s, 1H), 7.56 (s, 1H), 7.34-7.38 (m, 4H), 7.28-7.32 (m, 1H), 4.98 (s, 2H), 1.80-1.93 (m, 4H), 1.79 (s, 2H), 1.64 (t, J = 9,1 Hz, 2H), 1.57 (t, J = 8,8 Hz, 2H).

F. 4-aminobicyclo [2.2.1] heptane-1-carboxylic acid. 2 liter Parr bottle was filled with 4- (benzyloxycarbonylamino) bicyclo [2.2.1] heptane-1-carboxylic acid (105 g, 363 mmol), methanol (500 mL), 0.8 N hydrochloric acid (500 ml) and 10% palladium on carbon (38.6 g, 18.15 mmol, 50% hydration water). The reaction was conducted in a Parr shaker under a hydrogen pressure of 30 gpsi for 10 h until TLC analysis (10% methanol / ethyl acetate) indicated complete reaction. The catalyst was removed by filtration through a short plug of Celite and the plug washed thoroughly with water (4 × 100 mL). The filtrate was concentrated to give 4-aminobicyclo [2.2.1] heptane-1-carboxylic acid (56.3 g, 100%) as a moist white solid which was used in the next step without further purification; MS (ESI) m / z 156,2 [M + 1]⁺.

G. 4-hydroxybicyclo [2.2.1] heptane-1-carboxylic acid. 2-liter 3-proud round bottom flask was equipped with a mechanical stirrer, reflux condenser, temperature controller, J-KEM, and nitrogen inlet. The flask was filled with 4 aminobicyclo [2.2.1] heptane-1-carboxylic acid (56.3 g, 363 mmol) and 10% aqueous acetic acid (340 mL). The reaction mixture was cooled to 10 ° C and slowly treated over 45 minutes with sodium nitrate (75.0 g, 1.088 mol) in water (125 mL) via addition funnel. There was considerable gas evolution and the reaction mixture was stirred at 65 ° C overnight. The reaction mixture was cooled to 5 ° C and slowly treated for 30 min with potassium hydroxide (183 g, 3.265 mol) in methanol (400 mL) via addition funnel. The reaction mixture was stirred at 65 ° C for 5 h, When TLC analysis (10% methanol / ethyl acetate) indicated complete reaction. The reaction mixture was concentrated to remove methanol and the remaining aqueous mixture was extracted with ethyl acetate (2 × 400 mL). The aqueous layer was acidified to pH 3 using concentrated hydrochloric acid (210 ml) under cooling in an ice / water bath. The resulting solids (impurities) was filtered and washed with water (2 × 30 mL). The filtrate was extracted with ethyl acetate (10 × 400 ml), dried over sodium sulfate and concentrated to dryness to give 53 g (94%) of 4-hydroxybicyclo [2.2.1] heptane-1-carboxylic acid; MS (ESI) m / z 155,2 [M-1] using concentrated hydrochloric acid (210 ml) under cooling in an ice / water bath. The resulting solids (impurities) was filtered and washed with water (2 × 30 mL). The filtrate was extracted with ethyl acetate (10 × 400 ml), dried over sodium sulfate and concentrated to dryness to give 53 g (94%) of 4-hydroxybicyclo [2.2.1] heptane-1-carboxylic acid; MS (ESI) m / z 155,2 [M-1] using concentrated hydrochloric acid (210 ml) under cooling in an ice / water bath. The resulting solids (impurities) was filtered and washed with water (2 × 30 mL). The filtrate was extracted with ethyl acetate (10 × 400 ml), dried over sodium sulfate and concentrated to dryness to give 53 g (94%) of 4-hydroxybicyclo [2.2.1] heptane-1-carboxylic acid; MS (ESI) m / z 155,2 [M-1]^-.

N. Benzyl 4-hydroxybicyclo [2.2.1] heptan-1-ylcarbamate. 3-liter 3-necked round bottom flask was equipped with a mechanical stirrer, temperature controller, J-KEM, nitrogen inlet and a 125 ml addition funnel. The flask was flushed with nitrogen and filled 4-hydroxybicyclo [2.2.1] heptane-1-carboxylic acid (53 g, 339 mmol) and anhydrous toluene (350 mL). The reaction mixture was cooled to 10 ° C and treated with benzyl alcohol (175 mL, 1.695 mol). The reaction mixture was then slowly treated with DIEA (118 mL, 678 mmol) and diphenylphosphonyl azide (87.7 mL, 407 mmol). The reaction mixture was slowly heated to 50 ° C, when the gas evolution began. Heating mantle was removed and the reaction mixture was slowly giving an exotherm to 75 ° C with a significant gas evolution. The reaction mixture was heated to 110 ° C and stirred for 20 hours, When TLC analysis (10% methanol / ethyl acetate) indicated complete reaction. The reaction mixture was concentrated to remove solvent, and partitioned between ethyl acetate (1.2 L) and brine (700 mL). The organic layer was dried over sodium sulfate, concentrated and purified by silica gel chromatography (20-60% ethyl acetate / hexane) to give 61 g (69%) of benzyl 4-hydroxybicyclo [2.2.1] heptan-1-ylcarbamate; MS (ESI) m / z 260,1 [M-1]^-.

I. hydrochloride 4-aminobicyclo [2.2.1] heptan-1-ol. 2-liter Parr bottle was filled with benzyl 4-hydroxybicyclo [2.2.1] heptan-1-ylcarbamate (61 g, 233 mmol), methanol (400 ml) and water (200 mL). Parr bottle was flushed with nitrogen and filled with 10% palladium on carbon (25 g, 11.65 mmol, 50% hydration water). The reaction was conducted in hydrogen under a pressure of 30 gpsi on a Parr shaker for 3 h until TLC analysis (15% methanol / DCM with 2% ammonium hydroxide) indicated the reaction was complete. The reaction mixture was filtered through a plug of celite and concentrated to remove methanol. The resulting mixture was treated with aqueous 2N. hydrochloric acid (115 mL) to reach pH 1-2. The aqueous mixture was extracted with ethyl acetate (5 × 400 mL) to remove impurities. The aqueous mixture was concentrated to dryness and dried in a vacuum oven at 40 ° C overnight to give 36 91 g (97%) of 4-aminobicyclo [2.2.1] heptan-1-ol; MS (ESI) m / z 128,1 [M + 1]⁺.

J. 4- (tert-butylamino) -2- (4-gidroksibiciklo [2.2.1] heptanes-1-ylamino) pyrimidine-5-carboxamide. 4- (tert-butylamino) -2- (metilsulьfonil) pyrimidine-5-carboxamide (0.165 g, 0.606 mmolь; synthesis described in the present description) gidrohlorid 4-aminobicyclo [2.2.1] heptanes-1-ol (0.105 g, 0.644 mmolь) and DIЭA (0.337 mL, 1.931 mmolь) peremeshivali in DMF (8 ml) and heated at 90 ° C nochi. Rastvoritelь uparivali and tverdый ochiщali residue by column chromatography pomoщью with silikagelem (0-10% methanol in эtilacetate) with polucheniem celevogo product. (41 mg, 0.127 mmolь, 21%).¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 9.43 (br. S., 0H), 8.32 (s, 1H) 7.07 (br. S., 1H) 4.88 (br. S., 1H) 1.94 -2.14 (m, 2H), 1,61-1,87 (m, 6H), 1.49-1.60 (m, 2H) 1.42 (s, 9H). MS (ESI) m / z 320,0 [M + 1]⁺.

Example 47: 2 - ((1R, 4R) -4-Gidroksitsiklogeksilamino) -4- (3-methylbicyclo [1.1.1] pentane-1-ylamino) pyrimidine-5-carboxamide

<img file="00000153.jpg" he="37" wi="56" img-format="tif" img-content="undefined" />

A. 3-methylbicyclo [1.1.1] pentane-1-carboxylic acid. To a solution of 1-iodo-3-methylbicyclo [1.1.1] pentane (1.62 g, 7.79 mmol; prepared according to Eur J. Org Chem 1137-1155 (2000)...) In diethyl ether (26 mL) was added tert-butyllithium (9.16 mL, 15.57 mmol, 1.7 M in pentane) over a period of 40 minutes at -78 ° C. After stirring the reaction mixture for 1 h at this temperature, carbon dioxide gas was bubbled through the reaction mixture for 5 min and then was allowed to warm at room temperature. The reaction mixture was extracted twice with 5% aqueous sodium bicarbonate. The combined aqueous phases were acidified to pH 2-3 with concentrated hydrochloric acid at 0 ° C, saturated with sodium chloride and extracted with diethyl ether. The combined organic phases are dried,¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 12.21 (s, 1H), 1.82 (s, 6H), 1.14 (s, 3H).

B. Tert-butyl-3-methylbicyclo [1.1.1] pentan-1-ylcarbamate. Diphenylphosphonyl azide (0.340 mL, 1.577 mmol) was added dropwise to a solution of 3-methylbicyclo [1.1.1] pentane-1-carboxylic acid (0.199 g, 1.577 mmol) and TEA (0.220 mL, 1.577 mmol) in dry tert-butanol ( 6 mL). The solution was stirred at room temperature for 4 hours and then heated at reflux for 24 hours. The solvent was evaporated under reduced pressure and the solid residue was extracted with tert-butyl methyl ether three times. The combined organic phase was washed with a saturated aqueous sodium bikarboanata and dried over anhydrous magnesium sulfate. After filtration and evaporation of the solvent under reduced pressure, the solid residue was purified by column chromatography (0-5% ethyl acetate in hexane) to afford tert-butyl-3-methylbicyclo [1.1.¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 1.74 (s, 6H), 1.36 (s, 9H), 1.17 (s, 3H).

C. 3-methylbicyclo [1.1.1] pentan-1-amine hydrochloride. To a solution of tert-butyl-3-methylbicyclo [1.1.1] pentan-1-ylcarbamate (0.1 g, 0.507 mmol) in ethyl acetate (10 ml) was added hydrochloric acid (0.760 mL, 3.04 mmol, 4 M in dioxane ) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and the resulting solids were washed with diethyl ether and the resulting suspension was filtered to give the hydrochloride of 3-methylbicyclo [1.1.1] pentan-1-amine (0.04 g, 0.299 mmol, 59.1% yield).¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8.59 (br. S., 3H), 1.84 (s, 6H), 1.22 (s, 3H).

D. 2 - ((1R, 4R) -4-Gidroksitsiklogeksilamino) -4- (3-methylbicyclo [1.1.1] pentane-1-ylamino) pyrimidine-5-carboxamide. K peremeshivaemoy suspensions 2 - ((1R, 4R) -4-gidroksitsiklogeksilamino) -4- (metilsulyfinil) pyrimidine-5-carboxamide (0.25 g, 0.838 mmoly; synthesis described in the present activities as described) and gidrohlorida 3-methylbicyclo- [1.1 .1] pentan-1-amine (0.123 g, 0.922 mmoly) in DMF (3 mL) dobavlyali DIЭA (0,366 ml, 2,095 mmoly) and reaktsionnuyu smesy heated to 80 ° C over nochi. Sыruyu reaktsionnuyu smesy kontsentrirovali at ponizhennom davlenii and zatem ledyanuyu vodu (20 ml) dobavlyali k tverdomu ostatku. Poluchennuyu smesy эnergichno peremeshivali over 1 h and zatem obrazovavshiysya osadok filytrovali, promыvali water and dried in an efficient vacuum with polucheniem 2 - ((1R, 4R) -4-gidroksitsiklogeksilamino) -4- (3-methylbicyclo [1.1.1] pentane-1 ylamino) pyrimidine-5-carboxamide (0.222 g, 0.670 mmoly,¹H-NMR (400 MHz, DMSO-dg) δ hr. / Million 1,15-1,31 (m, 7H), 1.81-1.93 (m, 4H), 1.98 (s, 6H) , 3.35-3.44 (m, 1H), 3.54-3.63 (m, 1H), 4.56 (d, J = 4.29 Hz, 1H), 7.12 (d, J = 7.81 Hz, 1H), 8.35 (s, 1H), 9.35 (s, 1H); MS (ESI) m / z 332,4 [M + 1]⁺.

Example 48: 4 - ((1R, 3S) -3-Gidroksiciklogeksilamino) -2- (4-metiltetragidro-2H-pyran-4-ylamino) pyrimidine-5-carboxamide

<img file="00000154.jpg" he="41" wi="50" img-format="tif" img-content="undefined" />

A. 4 - ((1R, 3S) -3-Gidroksiciklogeksilamino) -2- (4-metiltetragidro-2H-pyran-4-ylamino) pyrimidine-5-carboxamide. 4 - ((1R, 3S) -3-Gidroksiciklogeksilamino) -2- (methylsulfonyl) pyrimidine-5-carboxamide (0.740 g, 2.354 mmol; synthesis are disclosed in the Present Description), hydrochloride of 4-metiltetragidro-2H-pyran-4-amine (0.892 g, 5.88 mmol), DIEA (1, 645 mL, 9.42 mmol) and NMP (20 ml) and obʺedinâli nagrevali in week 1 h at 180 ° C in a microwave oven. Be dissolved in koncentrirovali ponižennom pressure, and tverdyi tire Cleansing kolonočnoj hromatografiej (0-10% methanol in DCM) with receipt of 4 - ((1R, 3S) -3-gidroksiciklogeksilamino) -2- (4-metiltetragidro-2H-pyran-4- ylamino) pyrimidine-5-carboxamide (88 mg, 0.252 mmol, 10.70% output).¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8.96 (br. S., 1H), 8.35 (s, 1H), 6.76 (br. S., 1H), 4.65 (d, J = 4,69 Hz, 1H), 3.56 (dd, J = 3.32, 6.83 Hz, 4H), 3.40-3.47 (m, 1H), 2.20-2.29 (m, 2H) , 2.10 (d, J = 10,93 Hz, 1H), 1.76-1.89 (m, 2H), 1.66-1.73 (m, 1H), 1.50-1.59 (m, 2H), 1.39 (s, 3H), 1,16-1,26 (m, 1H), 1,03-1,12 (m, 3H). MS (ESI) m / z 350,4 [M + 1]⁺.

Example 49: 4 - ((1R, 3S) -3-hydroxycyclohexylamino) -2 - ((1R, 4R) -4 - [(²n₃) Methyloxy] ciklogeksilamino) pyrimidine-5-carboxamide

<img file="00000155.jpg" he="33" wi="61" img-format="tif" img-content="undefined" />

A. (1R, 4R) -4 - [(²n₃) Methyloxy] -N-tritiltsiklogeksanamin. To a solution of (1R, 4R) -4- (trityl-amino) cyclohexanol (2.34 g, 6.55 mmol) in dry THF (15 ml) was added sodium hydride (524 mg, 13.1 mmol, 60% in mineral oil) at 0 ° C. After the resultant mixture was stirred for 30 min at 0 ° C under nitrogen, was added dropwise a solution of iodine (²n₃) Methane (1.0 g, 6.89 mmol) in THF (5 mL) at 0 ° C. The resulting mixture was stirred at room temperature overnight under nitrogen, then poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated in vacuo to give the crude product which was purified by chromatography on a silica gel column (5% ethyl acetate in petroleum ether) to give the compound of the title (2.0 g, 5.35 mmol, 83% yield) as a white solid. MS (ESI) m / z 375,0 [M + 1]⁺.

B. (1R,4R)-4-[(²n₃) Methyloxy] cyclohexanamine. To a cooled (0 ° C) solution of (1R, 4R) -4 - [(²n₃) Methyloxy] -N-tritiltsiklogeksanamina (2.0 g, 5.35 mmol) in DCM (10 mL) was added TFA (3 mL) at 0 ° C. The resulting mixture was dark red. Was added triethylsilane (0.4 ml) as long as the resulting mixture became colorless. The reaction mixture was stirred at 0 ° C an additional 15 min. After removal of all volatile solvents in vacuo, the solid residue was further dried under high vacuum for 2 h to give the crude product as a white solid. The crude product was dissolved in ethyl acetate and aqueous hydrochloride solution (20 ml, 0.25 mol / l). The organic layer was removed, and the inorganic layer was washed with ethyl acetate twice. By the inorganic layer were added aqueous ammonium chloride (2 ml) and the mixture was stirred for 15 min. Concentration in vacuo gave the crude product as a white solid (706 mg, 5 35 mmol, 100% yield). MS (ESI) m / z 133,0 [M + 1].

C. 4 - ((1R, 3S) -3-hydroxycyclohexylamino) -2 - ((1R, 4R) -4 - [(2NC) methyloxy] cyclohexanamine) pyrimidine-5-carboxamide. A mixture of 4 - ((1R, 3S) -3-hydroxycyclohexylamino) -2- (methylsulfonyl) pyrimidine-5-carboxamide (160 mg, 0.5 mmol; synthesis described herein), (1R, 4R) -4- [ (²n₃) Methyloxy] -tsiklogeksanamina (132 mg, 1.0 mmol), DIEA (194 mg, 1.5 mmol) and NMP (1 mL) were combined and heated at 80 ° C overnight. The solvent was evaporated under reduced pressure and the solid residue was purified by column chromatography (0-15% methanol in DCM) to give the title product as a white powder (120 mg, 0.33 mmol, 63% yield).¹H-NMR (400 MHz, CD₃OD) δ hr. / Million 8.17 (s, 1H), 3,93-3,87 (m, 1H), 3.64 (s, 1H), 3.50 (d, J = 6,0 Hz , 1H), 3.13 (s, 1H), 2.22 (s, 1H), 2,06-1,72 (m, 7H), 1,29-0,99 (m, 8H); MS (ESI) m / z 367,3 [M + 1]⁺.

Example 50: 4- (tert-butylamino) -2 - ((1S, 4S) -4-gidroksi-4-metilciklogeksilamino) pyrimidine-5-carboxamide

<img file="00000156.jpg" he="30" wi="52" img-format="tif" img-content="undefined" />

A. 4- (tert-butylamino) -2 - ((1S, 4S) -4-gidroksi-4-metilciklogeksilamino) pyrimidine-5-carboxamide. 4- (tert-butylamino) -2- (metilsulьfonil) pyrimidine-5-carboxamide (0.110 g, 0.404 mmolь; synthesis described in the present description), (1S, 4S) -4-amino-1-metilciklogeksanol (0.055 g, 0.429 mmolь; poluchennый sootvetstvii in publications of the international trade patent applications PCT WO 2010027500) and DIЭA (0.225 mL, 1.287 mmolь) peremeshivali in DMF (5 ml) and heated at 90 ° C nochi. Rastvoritelь uparivali and tverdый ochiщali residue by column chromatography pomoщью with silikagelem (0-10% methanol in эtilacetate) with polucheniem celevogo product. (37 mg, 0.115 mmolь, 27%).¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 9,08-9,23 (m, 1H), 8,25-8,37 (m, 1H), 6,89-7,06 (m, 1H), 3,97-4,04 ( m, 1H), 3,46-3,62 (m, 1H) 1.48-1.71 (m, 6H), 1.40 (s, 9H), 1,19-1,36 (m, 2H), 1 10 (s, 4H). MS (ESI) m / z 322,4 [M + 1]⁺.

Example 51: 4 - ((1R, 3R) -3-Gidroksi-4,4-dimetiltsiklogeksilamino) -2- (1-metiltsiklopropilamino) pyrimidine-5-carboxamide

<img file="00000157.jpg" he="40" wi="45" img-format="tif" img-content="undefined" />

A. 2- (1-methylcyclopropylamine) -4- (methylthio) pyrimidine-5-carboxamide. To peremešivaemomu solution of 2- (1-methylcyclopropylamine) -4- (methylthio) pyrimidine-5-carbonitrile (0.653 g, 2.96 mmol, synthesis described in the Present Description) in DMSO (8 ml) dobavlâli 6 n sodium gidroksida Water solution of ( 2.470 ml, 14.82 mmol) and 30% Water solution of hydrogen perekisi (1.873 ml, 16.52 mmol) at 0 ° C. Thereafter peremešivali mix at 50 ° C and within 20 minutes, and then 100 ml of ethyl acetate razbavlâli and 30 ml of water. Udalâli layers, and Water layer ü ékstragirovali 50 ml of ethyl acetate. Émirats étilacetatnyj layer dried over magnesium sulfate bezvodnym, filʹtrovali and koncentrirovali to solid substances, å vakuumnoj dried in an oven at 45 ° C with receipt of 2- (1-methylcyclopropylamine) -4- (methylthio) pyrimidine-5-carboxamide (305 mg, 1.280 mmol, 43.2% of output).¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8,31-8,54 (m, 1H), 7,80-8,07 (m, 1H), 6,97-7,77 (m, 1H), 2.39 (br . s., 3H), 1.37 (s, 3H), 0,52-0,79 (m, 4H). MS (ESI) m / z 239,0 [M + 1]⁺.

B. 2- (1-Metiltsiklopropilamino) -4- (metilsulyfinil) pyrimidine-5-carboxamide. K peremeshivaemomu rastvoru 2- (1-metiltsiklopropilamino) -4- (methylthio) pyrimidine-5-carboxamide (305 mg, 1.280 mmoly) in the chloroform (25.6 mL) portsiyami dobavlyali 3-phenyl-2- (fenilsulyfonil) -1, 2-oxaziridine (502 mg, 1.920 mmoly). Poluchennыy light zheltыy simply entails peremeshivali at temperatures okruzhayushtey sredы over nochi. Reaktsionnыy simply entails kontsentrirovali at ponizhennom davlenii with polucheniem sыrogo product Vide belogo tverdogo substances. Dobavlyali эtilatsetat (10 ml), and vzvesy peremeshivali at komnatnoy temperature for 1 hour, filytrovali, promыvali эtilatsetatom and dried in vakuumnoy Pechi over neskolykih hour with polucheniem 2- (1-metiltsiklopropilamino) -4- (metilsulyfinil) pyrimidin-5- carboxamide (242 mg, 0.952 mmoly, 74.4% vыhod).¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8,35-8,90 (m, 2H), 7,88-8,14 (m, 1H), 7,28-7,59 (m, 1H), 2.74 (s , 3H), 1.32-1.46 (m, 3H), 0,68-0,84 (m, 2H), 0,50-0,70 (m, 2H). MS (ESI) m / z 255,0 [M + 1]⁺.

C. 4 - ((1R, 3R) -3-Hydroxy-4,4-dimethylcyclohexylamine) -2- (1-Methylcyclopropylamine) pyrimidine-5-carboxamide. To a stirred suspension of 2- (1-Methylcyclopropylamine) -4- (methylsulfinyl) pyrimidine-5-carboxamide (242 mg, 0.952 mmol) and the mixture hydrochloride (1R, 5R) -5-amino-2,2-dimethylcyclohexanol and hydrochloride ( 1S, 5S) -5-amino-2,2-dimethylcyclohexanol (222 mg, 1.237 mmol, synthesis described herein) in DMF (4,543 mL) was added DIEA (0.499 mL, 2.85 mmol) and the reaction mixture was heated to 90 ° C overnight. The crude reaction mixture was poured into 50 ml of ice water. Obtained solids slurry obtained for ~ 1 hour, filtered, washed with water and dried for several hours in a vacuum oven at 45 ° C to give a mixture of 4 - ((1R, 3R) -3-hydroxy-4,4-dimethylcyclohexylamine) -2- (1-Methylcyclopropylamine) pyrimidine-5-carboxamide and 4 - ((1R, 3R) -3-hydroxy-4,4-dimethylcyclohexylamine) -2- (1-Methylcyclopropylamine) pyrimidine-5-carboxamide (169 mg, 0.507 mmol, 53.3% yield). This material was separated using preparative chiral SFC, using a column ChiralPak AD-H, 250 × 30 mm ID with isocratic 40% ethanol + 0.1% ammonium hydroxide in CO₂ gradient at a flow rate of 60 ml / min and at 38 ° C. Isomer which was eluted faster, was designated as Peak 1 and 49 mg (0.147 mmol) was obtained. Isomer which elyurovalsya slower was labeled as peak 2 and 51 mg (0.153 mmol) was obtained. Peak 1:¹H-NMR (400 MHz, DMSO-d₆) Δ h. / M 8,71-9,02 (m, 1H), 8,21-8,43 (m, 1H), 7,03-7,54 (m, 1H), 4,44-4 58 (m, 1 H), 3,81-3,99 (m, 1H), 3,07-3,25 (m, 1H), 1,74-2,08 (m, 1H), 1.35 (s 8N), 0,87-0,97 (m, 3H), 0,77-0,86 (m, 3H), 0,62-0,70 (m, 2H), 0,47-0 59 (m, 2H). MS (ESI) m / z 334,2 [M + 1]⁺. Peak 2:¹Н-ЯМР (400 МГц, DMCO-d₆) Δ hr. / Million 8,72-9,00 (m, 1H), 8,18-8,46 (m, 1H), 7,12-7,60 (m, 1H), 4,38-4 61 (m, 1H), 3,76-3,98 (m, 1H), 3,04-3,26 (m, 1H), 1,75-2,10 (m, 1H), 1.35 (s, 8H), 0.92 (s, 3H), 0.82 (s, 3H), 0,61-0,72 (m, 2H), 0,47-0,60 (m, 2H). MS (ESI) m / z 334,2 [M + 1]⁺. By comparing the SAR forces with similar compounds of known absolute stereochemistry, as set forth herein, peak 1 was identified as the 4 - ((1S, 3S) -3-hydroxy-4,4-dimethylcyclohexylamine) -2- (1-Methylcyclopropylamine ) pyrimidine-5-carboxamide. Peak 2 was identified as the 4 - ((1R, 3R) -3-Hydroxy-4,4-dimethylcyclohexylamine) -2- (1-Methylcyclopropylamine) pyrimidine-5-carboxamide.

Example 52: 4- (bicyclo [1.1.1] pentan-2-ylamino) -2 - ((1R, 4R) -4-gidroksiciklogeksilamino) pyrimidine-5-carboxamide

<img file="00000158.jpg" he="33" wi="53" img-format="tif" img-content="undefined" />

A. 2-Fenilbitsiklo [1.1.1] pentan-2-ol. A stirred solution of cyclobutyl (phenyl) methanone (3.0 g, 18.8 mmol) in 800 ml of benzene was irradiated with a mercury lamp to 1000 V for 48 hours at room temperature under a nitrogen atmosphere. The solution was concentrated and the solid residue (3.1 g) was purified by column chromatography (10% -25% ethyl acetate in petroleum ether) to give the title product as a white solid (0.9 g , 5.6 mmol, yield: 30% ).¹H-ЯМР (300 МГц, CDCl₃) Δ hr. / Million 7,41-7,28 (m, 5H), 3.04 (s, 2H), 2.82 (dd, J1 = 10,2 Hz, J2 = 2,4 Hz, 1H) 2.09 (s, 1H), 1.78 (d, J = 2,4 Hz, 1H), 1.50 (d, J = 3,3 Hz, 1H), 1.33 (dd, J1 = 9.9, J2 = 3.3 Hz, 1H).

B. 2-Fenilbitsiklo [1.1.1] pentan-2-yl acetate. To a stirred solution of 2.7 g (16.8 mmol) of 2-fenilbitsiklo [1.1.1] pentan-2-ol in pyridine (15 ml) at 0 ° C was added dropwise acetyl chloride (1.5 mL, 21.0 mmol ) under a nitrogen atmosphere. The reaction mixture was stirred for 0.5 hours at 0 ° C and for 1 hour at room temperature. The solution was poured onto ice and extracted twice with 50 ml of diethyl ether. The combined ether solutions were washed with saturated aqueous sodium bicarbonate solution and a saturated aqueous solution of copper sulfate. After drying over anhydrous magnesium sulfate, the solution was concentrated, and the crude product was purified by column chromatography (0-5% ethyl acetate in petroleum ether) to give the desired product (2.7 g, 13.4 mmol, yield: 80%).¹Н-ЯМР (400 МГц, CDCl₃) Δ hr. / Million 7,47-7,26 (m, 5H), 3.31 (s, 2H), 2.43 (dd, J1 = 10,4 Hz, J2 = 2,8 Hz, 1H) 1.95 (s, 3H), 1.80 (d, J = 2,8 Hz, 1H), 1.66 (d, J = 3,2 Hz, 1H), 1.49 (dd, J1 = 10.4, J2 = 3.2 Hz, 1H).

C. 2-Fenilbitsiklo [1.1.1] pentane. A solution of 2-phenyl-bicyclo [1.1.1] pentan-2-yl acetate (2.7 g, 13.4 mol) in 50 ml of anhydrous ether was placed in a three-necked flask. The flask was cooled to -78 ° C and added to 150 ml of liquid ammonia. To the stirred mixture was added small pieces of sodium (0.62 g, 27.0 mmol) over 10 minutes. Stirring was continued until a blue highlight. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride solution (5 ml), and the solvent was allowed to evaporate overnight. To the solid residue was added pentane (40 mL) and the solution was washed with 30 ml of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated. The crude product was purified by column chromatography (100% pentane) to give the title compound as a colorless liquid (1.8 g, 12.5 mmol, yield: 93%).¹H-NMR (300 MHz, CDCl3) δ hr. / Million 7,40-7,21 (m, 5H), 3.48 (d, J = 6,9 Hz, 1H), 2.81 (s, 2H ), 2.20 (dd, J1 = 9,9 Hz, J2 = 2,7 Hz, 1H), 2.00 (d, J = 2,1 Hz, 1H), 1,94-1,85 (m , 2H).

D. Bicyclo [1.1.1] pentane-2-carboxylic acid. A mixture of 2-fenilbitsiklo [1.1.1] pentane (2.8 g, 19.4 mmol), ruthenium oxide (IV) (0,1 g, 0.75 mmol), sodium periodate (41.5 g, 194 mmol) , water (155 ml), perhlormetana (110 ml) and acetonitrile (110 ml) was stirred for 4 days. To the mixture was added DCM (200 mL) and the solids were removed by filtration. The mother liquor was basified with aqueous sodium hydroxide (1M) and the organic solution was removed under reduced pressure. The inorganic layer is a solid precipitate was extracted with diethyl ether (100 ml × 2), and the aqueous phase was acidified with aqueous hydrochloric acid (2M) to pH &lt;3, then extracted with diethyl ether (100 mL × 5). The organic layers were combined and concentrated to give the crude acid as a yellow liquid.¹Н-ЯМР (300 МГц, CDCl₃) Δ hr. / Million 2.97 (d, J = 7,5 Hz, 1H), 2.82 (s, 2H), 2.49 (dd, J1 = 7,2 Hz, J2 = 3,3 Hz , 1H), 1.92 (dd, J1 = 7,2 Hz, J2 = 3,3 Hz, 1H), 1,79-1,76 (m, 2H).

E. hydrochloride bicyclo [1.1.1] pentan-2-amine. To a stirred solution bicyclo [1.1.1] pentane-2-carboxylic acid (1.0 g, 8.9 mmol) in anhydrous toluene (25 ml) and 2-methylpropan-2-ol (5 mL) was added DIEA (2, 3 g, 17.8 mmol) and diphenyl phosphorazidate (2.9 g, 10.7 mmol). The mixture was heated at 90 ° C for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the solid residue was purified by column chromatography (10% ethyl acetate in petroleum ether) to give crude tert-butylbicyclo [1.1.1] pentan-2-ylcarbamate. The crude product was dissolved in 15 ml of hydrochloric acid (1M in methanol) and the solution was stirred at room temperature for 16 hours. The solution was concentrated and the solid residue was suspended in 50 ml of diethyl ether. The mixture was stirred for 15 min, and the precipitates were collected and dried to give compound¹Н-ЯМР (ie ДМСО₆) Δ hr. / Million 8.58 (br. S, 3H), 3.35 (s, 1H), 2.62 (s, 2H), 2,60-2,57 (m, 1H), 1, 90 (t, J = 5,0 Hz, 1H), 1.79 (d, J = 2,4 Hz, 1H), 1.50 (dd, J1 = 10,0 Hz, J1 = 2,8 Hz, 1H).

F. 4- (Bicyclo [1.1.1] pentan-2-ylamino) -2 - ((1R, 4R) -4-gidroksiciklogeksilamino) pyrimidine-5-carboxamide. A mixture of 2 - ((1R, 4R) -4-gidroksiciklogeksilamino) -4- (methylsulfonyl) pyrimidine-5-carboxamide (300 mg, 0.95 mmol; synthesis are disclosed in the Present Description), hydrochloride bicyclo [1.1.1] pentan 2-amine (220 mg, 1.84 mmol) and DIEA (300 mg, 2.33 mmol) in NMP (3 ml) at 100 ° nagrevali S in week 16 h. Cleansing Polučennuû mix twice by preparative vysokoéffektivnoj židkoj Chromatography (5-80% acetonitrile in water) with receipt of syrogo product (105 mg), which perekristallizovyvali from chloroform, with receipt of celevogo Connection (85.2 mg, 0.27 mmol, output: 28 %).¹H-NMR (400 MHz, CD₃. OD) δ h / million: 8.33 (s, 1H), 4.19 (d, J = 6,8 Hz, 1H), 3,77-3,74 (m, 1H), 3,60- 3.57 (m, 1H), 2.67 (s, 2H), 2.54 (dd, J1 = 9,6 Hz, J2 = 3,2 Hz, 1H), 2,07-1,88 (m , 6H), 1.66 (d, J = 9,6 Hz, 1H), 1,39-1,34 (m, 4H); MS (ESI) m / z 318,1 [M + H]⁺.

Example 53: 2 - ((S) -sec-butylamino) -4 - (((1R, 3R, 4R) -3-gidroksi-4-metilciklogeksil) amino) pyrimidine-5-carboxamide

<img file="00000159.jpg" he="40" wi="50" img-format="tif" img-content="undefined" />

A. 4 - ((1R, 3R, 4R) -3-Gidroksi-4-metiltsiklogeksilamino) -2- (methylthio) pyrimidine-5-carboxamide. 4 - ((1R, 3R, 4R) -3-Gidroksi-4-metiltsiklogeksilamino) -2- (methylthio) pyrimidine-5-carbonitrile (0.335 g, 1,203 mmoly; synthesis described in the present activities as described) rastvoryali in DMSO (3 mL) . Zatem at komnatnoy air temperature dobavlyali vodnыy simply entails gidroksida sodium (1.003 ml, 6 N, 6.02 mmoly) and vodnыy simply entails perekisni hydrogen (0.682 mL, 6.02 mmoly, 30%). Zatem reaktsionnuyu smesy peremeshivali at 50 ° C for 2 h. Reaktsionnuyu smesy cooled at komnatnoy temperature, and ee vыlivali in 100 ml ledyanoy vodы. Belыy osadok sobirali and dvazhdы promыvali water. Tverdoe substance dried polucheniem 4 - ((1R, 3R, 4R) -3-gidroksi-4-methyl-tsiklogeksilamino) -2- (methylthio) pyrimidine-5-carboxamide (0.260 g, 0.877 mmoly, 72.9% vыhod) ; MS (ESI) m / z 297,7 [M + 1]⁺.

B. 4 - ((1R, 3R, 4R) -3-Gidroksi-4-metiltsiklogeksilamino) -2- (metilsulyfonil) pyrimidine-5-carboxamide. 4 - ((1R, 3R, 4R) -3-Gidroksi-4-metiltsiklogeksilamino) -2- (methylthio) pyrimidine-5-carboxamide (315 mg, 1.063 mmoly) rastvoryali in NMP (4 mL) and cooled to 0 ° C and zatem portsiyami dobavlyali mCPBA (476 mg, 2,126 mmoly). Cherez 1 h 75 ml ledyanoy vodы adjacent dobavlyali k reactionary mixtures and vzvesy ostavlyali peremeshivatysya over 2 h and zatem otfilytrovыvali belыy osadok. Filytrat zatem kondensirovali in ponizhennom davlenii dlya succeeded vodы. Simply entails NMP adjacent ispolyzovali in sleduyushtey stages putative kolichestvennoe transformation in tselevoy product; MS (ESI) m / z 329,4 [M + 1]⁺.

C. 2 - ((S) -sec-butylamino) -4 - (((1R, 3R, 4R) -3-hydroxy-4-methylcyclohexyl) amino) pyrimidine-5-carboxamide. To a stirred suspension of 4 - ((1R, 3R, 4R) -3-hydroxy-4-methylcyclohexylamine) -2- (methylsulfonyl) pyrimidine-5-carboxamide (0.2 g, 0.609 mmol) in DMF (3 mL) was added ( S) - (+) - sec-butylamine (0.305 mL, 3.05 mmol) and the reaction mixture was heated to 90 ° C overnight. The crude reaction mixture was concentrated under reduced pressure and then purified using reverse-phase semi-preparative HPLC (5-75% methanol + 0.1% formic acid in water + 0.1% formic acid, over 26 min). Fractions containing product were concentrated under reduced pressure and the resulting solid was again dissolved in methanol (5 ml) was passed through a SPE tube with a polymer Varian StratoSpheres HCO3- to remove formic acid (0,¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 0,80-1,24 (m, 15H), 1.35-1.45 (m, 1H) 1.54 (br. S., 1H) 1.66 (d, J = 12 , 89 Hz, 1H) 1.92 (br. s., 1H) 2.14 (br. s., 1H) 2.97 (br. s., 1H), 3,71-3,99 (m, 1H ) 4.55 (d, J = 5,86 Hz, 1H) 6.96 (br s, 1H) 8.34 (s, 1H), 8.90 (br s, 1H)....; MS (ESI) m / z 322,5 [M + 1]⁺.

Example 54: 2 - ((1R, 4R) -4-Gidroksitsiklogeksilamino) -4- (1-metiltsiklobutilamino) pyrimidine-5-carboxamide

<img file="00000160.jpg" he="32" wi="52" img-format="tif" img-content="undefined" />

A. 2 - ((1R, 4R) -4-hydroxycyclohexylamino) -4- (1-metiltsiklobutilamino) pyrimidine-5-carboxamide. To a mixture of 2 - ((1R, 4R) -4-hydroxycyclohexylamino) -4- (methylsulfinyl) pyrimidine-5-carboxamide and 2 - ((1R, 4R) -4-hydroxycyclohexylamino) -4- (methylsulfonyl) pyrimidin-5- carboxamide (total 1.414 mmol; synthesis described herein) in NMP (18 ml) was added 1-metiltsiklobutanamina hydrochloride (0.189 g, 1.556 mmol) and DIEA (0.988 mL, 5.66 mmol). The resulting solution was heated at 100 ° C overnight. Ethyl acetate and water to the reaction mixture, and the layers removed. The ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to an oil which was purified by silica gel chromatography (0-20% methanol in DCM) to give 2 - ((1R,¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 9.13 (s, 1H), 8.33 (s, 1H) 7.57 (br. S., 1H) 7.01 (d, J = 7,81 Hz, 2 H) 4, 53 (d, J = 4,69 Hz, 1H) 3.58 (br. s., 1H) 2.32 (d, J = 10,54 Hz, 2H), 1.94-2.11 (m, 2H ) 1.84 (d, J = 5,08 Hz, 6H), 1.52 (s, 3H), 1,05-1,36 (m, 4H). MS (ESI) m / z 320,1 [M + 1]⁺.

Example 55 4- (Bicyclo [2.1.1] Hexane-1-ylamino) -2 - (((1 R, 4R) -4-gidroksiciklogeksil) amino) pyrimidine-5-carboxamide

<img file="00000161.jpg" he="33" wi="54" img-format="tif" img-content="undefined" />

A. 2-methylbicyclo [2.2.1] heptane-2-ol. To a solution of bicyclo [2.2.1] heptan-2-one (25 g, 0.23 mol) in diethyl ether (250 mL) was added methylmagnesium bromide THF solution (3 mol / l, 90 ml, 0.27 mol) in for 1 h at 0 ° C. The reaction mixture was stirred an additional 30 min, heating at room temperature. The reaction mixture was quenched with 40 mL of saturated aqueous ammonium chloride. The resulting mixture was extracted with diethyl ether (3 × 80 mL). The organic layers were combined and concentrated to give the desired product (26 g, 0.205 mol, yield: 90%).¹Н-ЯМР (400 МГц, CDCl₃) Δ hr. / Million 2.20 (s, 1H), 2.01 (s, 1H), 1.94 (s, 1H), 1,61-1,49 (m, 3H), 1,34- 1.20 (m, 7H).

B. 1-methylbicyclo [2.2.1] heptane-2-ol. To a solution of 2-methyl-bicyclo [2.2.1] heptan-2-ol (26 g, 0.20 mol) in acetic acid (50 g, 0.83 mol) was added 1 ml of sulfuric acid. The mixture was refluxed for 3 hours and then concentrated under reduced pressure. The solid residue was poured into 100 ml of water. The resulting mixture was extracted with ethyl acetate (3 × 50 mL) and the combined extracts were washed with saturated aqueous sodium bicarbonate (100 ml), brine (100 mL) and then dried over anhydrous sodium sulfate. Removal of the solvent gave 1-methylbicyclo [2.2.1] heptan-2-yl acetate (31 g, 0.173 mol, yield: 89%) as a colorless oil which was used without further purification.

A mixture of 1-methylbicyclo [2.2.1] heptan-2-yl acetate (31 g, 0.17 mol) and aqueous sodium hydroxide (5%, 250 ml) was refluxed for 2 hours. After that was cooled at room temperature, the reaction mixture was extracted with diethyl ether (3 × 100 mL) and the combined organic layers were dried over magnesium sulfate and concentrated to give the title compound (21 g, 0.167 mol, yield: 82%) which was used in the next step without further purification. ¹Н-ЯМР (400 МГц, CDCl₃) Δ hr. / Million 3,47-3,46 (m, 1H), 2,16-2,14 (m, 1H), 1.81-1.75 (m, 1H), 1,57-1 52 (m, 1H), 1,43-1,30 (m, 3H), 1.15 (br. s, 3H), 1,01-0,97 (m, 2H).

S. methylenebicyclo [2.2.1] heptan-1-yl trifluoromethanesulfonate. To a solution of oxalyl dichloride (31.75 g, 0.25 mol) in DCM (300 ml) was added at -78 ° C in the following order of DMSO (19.5 g, 0.25 mol), 1-methylbicyclo solution [2.2. 1] heptane-2-ol (21 g, 0.167 mol) in DCM (50 mL) and then triethylamine (50 g, 0.5 mol). The mixture was stirred at room temperature overnight and then poured into 200 ml of water. The resulting mixture was extracted with DCM (2 × 100 mL). The combined extracts were washed with saturated aqueous sodium bicarbonate (50 ml), brine (50 mL) and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave a crude methylbicyclo [2.2.1] heptan-2-one, which was purified by chromatography on a silica gel column (10% ethyl acetate in petroleum ether) to afford 12.4 g (0.10 mol, yield:

To a solution methylbicyclo [2.2.1] heptan-2-one (26 g, 0.209 mol) and 2,6-di-tert-butyl-4-methylpyridine (64 g, 0.315 mol) in DCM (300 ml) was added dropwise trifluoromethanesulfonic anhydride (88 g, 0.315 mol) in DCM (50 mL) at 0 ° C. The reaction mixture was stirred at room temperature for 24 hours. The mixture was poured into water and extracted with DCM (2 × 100 mL). The combined extracts were washed with 10% hydrochloric acid (3 × 100 mL), saturated aqueous sodium bicarbonate (50 ml), brine (50 mL) and dried over sodium sulfate. Concentration under reduced pressure gave a crude product which was purified by chromatography on a silica gel column (100% n-pentane) to afford the desired product (7.6 g, 0.03 mol, 14%).¹Н-ЯМР (400 МГц, CDCl₃):... Δ h / million 5.15 (br s, 1H), 4.89 (br s, 1H), 2,51-2,39 (m, 2H), 2,26-2,17 ( m, 2H), 2,12-2,05 (m, 2H), 1,99-1,85 (m, 2H), 1,53-1,50 (m, 1H).

D. 2-oxobicyclo [2.2.1] heptan-1-yl trifluoromethanesulfonate. A solution methylenebicyclo [2.2.1] heptan-1-yl trifluoromethanesulfonate (7.6 g, 0.03 mol) in methanol (100 ml) was cooled to -40 ° C and the reaction mixture was passed through a stream of ozone. When the mixture became a blue color, ozone was removed by passing a stream of argon through the solution for 10 min. To the mixture was added dimethylsulfide (5 mL) and the reaction mixture was allowed to warm to room temperature. The resulting mixture was poured into water and extracted with DCM (2 × 40 mL). The combined extracts were washed with saturated brine (100 ml) and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure to give a crude product which was purified by chromatography on a silica gel column (10% ethyl acetate in petroleum ether) to give the desired product (4.6 g, 18.1 mmol, yield:¹Н-ЯМР (400 МГц, CDCl₃) Δ hr. / Million 2.73 (br. S, 1H), 2,44-2,34 (m, 2H), 2,26-2,13 (m, 4H), 2,06-2,02 (m, 1H), 1,70-1,66 (m, 1H).

E. Bicyclo [2.1.1] hexane-1-carboxylic acid. A mixture of 2-oxobicyclo [2.2.1] heptan-1-yl trifluoromethanesulfonate (4.6 g, 18.1 mmol) in 600 ml of ethanol / water (60% w / w) and TEA (3.7 g, 36.2 mmol) was heated at 130 ° C for 100 h. The mixture was concentrated under reduced pressure and the solid residue was poured into aqueous hydrochloric acid (1 mol / l, 150 ml) and extracted with diethyl ether (3 × 100 mL). The combined extracts were washed with saturated brine (100 ml) and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure to give a crude product which was purified by chromatography on a silica gel column (10% ethyl acetate in petroleum ether) to give the desired product (1.00 g, 8.09 mmol, yield: 45%).¹Н-ЯМР (400 МГц, CDCl₃) D ч. / Млн 2,47-2,45 (м, 1Н), 1,94-1,90 (м, 4Н), 1,79-1,74 (м, 2Н), 1,37-1 , 35 (м, 2Н).

F. Benzyl bicyclo [2.1.1] hexane-1-ylcarbamate. To a solution of bicyclo [2.1.1] hexane-1-carboxylic acid (1.0 g, 8.09 mmol) in dioxane (20 mL) was added DIEA (2.5 g, 12.4 mmol), diphenylphosphoryl azide (3.1 g, 11.2 mmol) and phenylmethanol (1.5 g, 14.2 mmol). The mixture was stirred at 80 ° C overnight under a nitrogen atmosphere and concentrated under reduced pressure. The solid residue was purified by chromatography on a silica gel column (10% ethyl acetate in petroleum ether) to give the desired product (1.2 g, 5.2 mmol, yield: 65%). MS (ESI) m / z = 231,2 [M + H]⁺.

G. Bicyclo [2.1.1] hexan-1-amine hydrochloride. To a solution of benzyl bicyclo [2.1.1] hexane-1-ylcarbamate (1.2 g, 5.2 mmol) in methanol (30 mL) was added palladium on carbon (10%, 0.1 g). The reaction mixture was stirred at 50 ° C in a hydrogen atmosphere (50 psi. Inch) overnight and filtered through celite. To the filtrate was added hydrochloric acid solution (10% in methanol, 20 mL). The mixture was concentrated and the solid residue was suspended in THF (20 mL). The mixture was stirred at room temperature for 1 h The residue was collected and dried to give the object product (550 mg, 4.13 mmol, yield: 79%)..¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8.73 (br. S, 3H), 2.4 (br. S, 1H), 1,71-1,69 (m, 6H), 1,32-1,31 (m , 2H). MS (ESI) m / z = 98,2 [M + H]⁺.

H. 4- (Bicyclo [2.1.1] hexane-1-ylamino) -2- (methylthio) pyrimidine-5-carbonitrile. To a stirred solution of 4-chloro-2- (methylthio) pyrimidine-5-carbonitrile (427 mg, 2.3 mmol) in 1,4-dioxane (10 mL) was added DIEA (890 mg, 6.9 mmol) and bicyclo hydrochloride [2.1.1] hexan-1-amine (320 mg, 2.4 mmol). The resulting mixture was stirred at 60 ° C for 2 hours. The reaction mixture was poured into saturated saline solution and then extracted with ethyl acetate (20 ml) three times. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product which was purified by chromatography on a silica gel column (15% ethyl acetate in petroleum ether) to give the desired product (502 mg, 2.0 mmol, 89% yield ). MS (ESI) m / z = 247,2 [M + 1]⁺.

I. 4- (Bicyclo [2.1.1] Hexane-1-ylamino) -2- (methylthio) pyrimidine-5-carboxamide. To a solution of 4- (bicyclo [2.1.1] Hexane-1-ylamino) -2- (methylthio) pyrimidine-5-carbonitrile (502.0 mg, 2.0 mmol) in DMSO (5 ml) solution Water dobavlâli perekisi vodoroda (1.2 g, 30%, 10.2 mmol) and Water Sodium gidroksida solution (1.7 ml, 6 mol / l, 10.2 mmol) at 0 ° C. Peremešivali mix at 50 ° C for 15 min and then quenched, dobavlââ water (30 ml). Sformirovavšeesâ tverdoe substance gathering place and dried under vacuum with receipt celevogo product (500 mg, 1.9 mmol, 93% output). MS (ESI) m / z = 265.3 [M + 1]⁺.

J. 4- (Bicyclo [2.1.1] Hexane-1-ylamino) -2- (methylsulfinyl) pyrimidine-5-carboxamide and 4- (bicyclo [2.1.1] Hexane-1-ylamino) -2- (methylsulfonyl) pyrimidine-5-carboxamide. To a solution of 4- (bicyclo [2.1.1] Hexane-1-ylamino) -2- (methylthio) pyrimidine-5-carboxamide (500 mg, 1.9 mmol) in TGF (10 ml) at 0 ° C Porcia dobavlâli mCPBA (490 mg, 2.8 mmol). After 1 h, reakcionnuû mix koncentrirovali. Received Syro substance Cleansing via column chromatography on silica gel with (5-10% methanol in DCM) with receipt of a mixture of 510 mg želaemoj. MS (ESI) m / z = 281.3, 297.3 [M + 1]⁺.

K. 4- (Bicyclo [2.1.1] Hexane-1-ylamino) -2 - (((1 R, 4R) -4-gidroksiciklogeksil) amino) pyrimidine-5-carboxamide. To a mixture of 4- (bicyclo [2.1.1] Hexane-1-ylamino) -2- (methylsulfinyl) pyrimidine-5-carboxamide and 4- (bicyclo [2.1.1] Hexane-1-ylamino) -2- (methylsulfonyl) pyrimidine-5-carboxamide (200 mg, about 0.71 mmol) and (1R, 4R) -4-aminociklogeksanol (123.3 mg, 1.02 mmol) in NMP (10 ml) dobavlâli DIEA (183.0 mg, 1.42 mmol). Polučennuû peremešivali blend at 100 ° C in the night a week. Cleansing Reakcionnuû mix via preparative HPLC with receipt celevogo product (187.3 mg, 0.56 mmol, 72% output).¹H-NMR (400 MHz, CD₃OD) δ hr. / Million 8.29 (s, 1H), 3.77 (m, 1H), 3.60 (m, 1H), 2.43 (s, 1H), 2,07-1,93 (m, 8H), 1,79-1,77 (m, 2H), 1.60 (s, 2H), 1,41-1,35 (m, 4H). MS (ESI) m / z = 332,2 [M + H]⁺.

Example 56: 4- (1-Étilciklopentilamino) -2 - ((1R, 4R) -4-gidroksiciklogeksilamino) pyrimidine-5-carboxamide

<img file="00000162.jpg" he="35" wi="52" img-format="tif" img-content="undefined" />

A. ethylcyclopentyl-3-ene carboxylate. To a stirred solution of cyclopent-3-ene carboxylate (10 g, 89.3 mmol) in anhydrous ethanol (30 ml) was added sulfur dichloride (15.9 g, 134 mmol) at 0 ° C. The reaction mixture was stirred at room temperature overnight and then concentrated. The solid residue was poured into water. The resulting mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the solid residue was purified by chromatography on a silica gel column (2.5% ethyl acetate in petroleum ether) to give the desired product (6.7 g, 47.9 mmol, yield = 54%) as a yellow oil which was used in the next step without further purification.¹Н-ЯМР (400 МГц, CDCl₃) Δ hr. / Million 5.66 (s, 2H), 4,18-4,10 (m, 2H), 3,16-3,05 (m, 1H), 2.66 (s, 2H) 2.63 (s, 2H), 1,29-1,24 (t, J = 9,4, 3H).

B. Ethyl 1-ethylcyclopentyl-3-ene carboxylate. To a solution of diisopropylamine (10 mL, 72 mmol) in anhydrous THF (50 mL) was added n-butyllithium (29 mL, 72 mmol, 2.5 M solution in hexanes) for 20 min at -78 ° C. The mixture was stirred at 0 ° C under a nitrogen atmosphere for 1 h. Diizopropilamidlity freshly added to the mixture ethylcyclopentyl-3-ene carboxylate (6.7 g, 47.9 mmol) in anhydrous THF (50 mL) for 20 minutes at -78 ° FROM. After a further 1 hour at the same temerature was added iodoethane (11.2 g, 72 mmol) for 20 min. The mixture was then stirred at room temperature for 2 h and quenched with saturated aqueous ammonium chloride. The aqueous layer was extracted with ether (3 × 100 mL). The combined organic layers were washed with dilute hydrochloric acid (1N), then washed with saturated brine, dried over anhydrous sodium sulfate and filtered. Concentration gave compound the title compound (7 g, crude) which was used in the next step without further purification.¹Н-ЯМР (400 МГц, CDCl₃) Δ hr. / Million 5.60 (s, 2H), 4,21-4,12 (m, 2H), 2.92-2.84 (m, 2H), 2,31-2,25 (m , 2H), 1.75-1.67 (m, 2H), 1,29-1,24 (m, 3H), 0,88-0,82 (m, 3H).

C. 1-ethylcyclopentyl-3-ene carboxylate. A solution of ethyl 1-ethylcyclopentyl-3-ene carboxylate (3.5 g, 20.8 mmol) and aqueous sodium hydroxide (20.8 ml, 2 mol / L) in methanol (30 ml) was stirred at 80 ° C for 2 hours and then concentrated. The solid residue was poured into water and extracted with ether (3 × 100 mL). The aqueous layer was acidified with 4 mol / L aqueous hydrochloric acid until pH &lt;3 and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and filtered. Concentration under reduced pressure gave a crude product which was purified by chromatography on a silica gel column (5% ethyl acetate in petroleum ether) to give the compound of the title (1.9 g, 13.6 mmol, 65.5% yield).¹Н-ЯМР (400 МГц, CDCl₃) δ ч./млн 5,61 (с, 2Н), 2,91 (д, J=14,8, 2Н), 2,32 (д, J=14,4, 2Н), 1,78-1,72 (м, 2Н), 0,92-0,88 (т, J=7,4, 3Н).

D. Benzyl (1-ethylcyclopentyl-3-en-1-yl) carbamate. To a solution of 1-ethylcyclopentyl-3-ene carboxylate (1.9 g, 13.6 mmol) in dioxane (30 mL) was added DIEA (5.3 g, 41 mmol), diphenylphosphoryl azide (4.5 g, 16.3 mmol ) and benzyl alcohol (2.2 g, 20.4 mmol). The mixture was stirred at 80 ° C overnight and then concentrated under reduced pressure. The solid residue was purified by chromatography on a silica gel column (2.5% ethyl acetate in petroleum ether) to give the product of the title (1.3 g, 5.3 mmol, yield: 39%). MS (ESI) m / z = 246,2 [M + 1]⁺.

E. hydrochloride 1-etiltsiklopentanamin. To a solution of benzyl (1-ethylcyclopentyl-3-en-1-yl) carbamate (1.3 g, 5.3 mmol) in methanol (20 mL) was added palladium on carbon (130 mg, 10%). The reaction mixture was stirred at 50 ° C in a hydrogen atmosphere overnight. A solution of hydrochloric acid (20 mL, 1 mol / l in methanol) was added to the reaction mixture, and the reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure to give the crude product (900 mg), which was used in the next step without further purification. MS (ESI) m / z = 114,2 [M + H]⁺.

F. 4- (1-Etiltsiklopentilamino) -2- (methylthio) pyrimidine-5-carbonitrile. To a stirred solution of 4-chloro-2- (methylthio) pyrimidine-5-carbonitrile (984 mg, 5.3 mmol) in DMSO (10 mL) was added DIEA (2.1 g, 15.9 mmol) and 1-hydrochloride etiltsiklopentanamin (900 mg, crude). The resulting mixture was stirred at 60 ° C for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give crude product. The crude product was purified by chromatography on a silica gel column (5% ethyl acetate in petroleum ether) to give the title product as a yellow oil (830 mg, 3.2 mmol, 53.5% yield). MS (ESI) m / z = 263,2 [M + H]⁺.

G. 4- (1-Étilciklopentilamino) -2- (methylthio) pyrimidine-5-carboxamide. To a solution of 4- peremešannomu (1-étilciklopentilamino) -2- (methylthio) pyrimidine-5-carbonitrile (830 mg, 3.2 mmol) in DMSO (10 ml) solution Water dobavlâli perekisi hydrogen (1.8 g, 30%, 16 mmol), and Water Sodium gidroksida solution (2.7 ml, 6 mol / l, 16 mmol) at 0 ° C. Peremešivali mix at 50 ° C for 15 min and razbavlâli water. Mixture ékstragirovali ethyl acetate (3 × 100 mL). Émirats organic layers promyvali nasyŝennym solevym solution, dried over sodium sulphate and bezvodnym filʹtrovali. Koncentrirovanie in ponižennom pressure gave crude product, which Cleansing via column chromatography on silica gel with (5% methanol in DCM) with receipt of celevogo product in the form of a rigid white substances (800 mg, 2.9 mmol, 90% output). MS (ESI) m / z = 281.2 [M + 1].

H. 4- (1-Étilciklopentilamino) -2- (methylsulfonyl) pyrimidine-5-carboxamide. At 0 ° C to a solution of 4- (1-étilciklopentilamino) -2- (methylthio) pyrimidine-5-carboxamide (800 mg, 2.9 mmol) in TGF (30 ml) Porcia dobavlâli mCPBA (873 mg, 4.3 mmol ). After 1 h, reakcionnuû koncentrirovali blend, and recieved raw Cleansing via column chromatography on silica gel with (5% methanol in DCM) with receipt of celevogo product (800 mg, 2.56 mmol, 90% output). MS (ESI) m / z = 313.2 [M + 1]⁺.

I. 4- (1-Etiltsiklopentilamino) -2 - ((1R, 4R) -4-hydroxycyclohexylamino) pyrimidine-5-carboxamide. To a mixture of 4- (1-etiltsiklopentilamino) -2- (methylsulfonyl) pyrimidine-5-carboxamide (200 mg, 0.64 mmol) and (1R, 4R) -4-aminocyclohexanol (115 mg, 1 mmol) in NMP (10 mL) was added DIEA (255 mg, 1.98 mmol). The resulting mixture was stirred at 100 ° C overnight. The reaction mixture was purified by preparative HPLC to give the desired product (117.0 mg, 0.34 mmol, yield 51%).¹H-NMR (400 MHz, CD₃OD) δ hr. / Million 8.17 (s, 1H), 3.66 (s, 1H), 3.46 (s, 1H), 2,06-2,04 (m, 2H), 1.98 -1.89 (m, 6H), 1,66-1,58 (m, 6H), 1,26-1,24 (m, 4H), 1,77-0,73 (t, J = 7, 2 Hz, 3H); MS (ESI) m / z = 348 2 [M + 1]⁺.

Example 57: 4 - (((1 R, 3S) -3-Gidroksiciklogeksil) amino) -2 - ((4-methoxybicyclo [2.2.2] octan-1-yl) amino) pyrimidine-5-carboxamide

<img file="00000163.jpg" he="38" wi="56" img-format="tif" img-content="undefined" />

A. Dimethyl-1- (2-chloroethyl) -cyclohexane-1,4-dicarboxylate. To a stirred solution of cyclohexane-1,4-dicarboxylic acid (100 g, 0.58 mol) in anhydrous methanol (800 mL) was added sulfur dichloride (208 g, 1.75 mol) at 0 ° C. The reaction mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The solid residue was poured into water. The resulting mixture was extracted with ethyl acetate (200 ml × 3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and filtered. Concentration gave a crude dimethylcyclohexane-1,4-dicarboxylate (105 g, 0.53 mol, yield 90.5%) which was used without further purification.

To a solution of diisopropylamine (88 ml, 0.62 mol) in anhydrous THF (500 mL) was added n-butyllithium (240 mL, 0.6 mol, 2.5 M solution in hexanes) for 20 min at -78 ° C. The mixture was stirred at 0 ° C under a nitrogen atmosphere for 30 min.

To the above mixture of raw dimethylcyclohexane-1,4-dicarboxylate (100 g, 0.5 mol) and hexamethylphosphoramide (360 mL, 2 mol) in anhydrous THF (800 mL) was added a solution of freshly prepared lithium diisopropylamide (preparation described above) for 30 min at -40 ° C. After stirring for 1 h at this temperature, was added 1-bromo-2-chloroethane (42 mL, 0.5 mol) over 1. The mixture was stirred for 3 hours at -78 ° C and then stirred overnight at room temperature. The reaction mixture was quenched by addition of aqueous hydrochloric acid solution (3N, 420 mL). The solvent was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate (200 ml × 3). The combined extracts were washed with brine (2 × 300 ml) and dried over sodium sulfate. Concentration gave compound the title compound (116 g,¹Н-ЯМР (400 МГц, CDCl₃) Δ hr. / Million 3.72 (s, 3H), 3.65 (s, 3H), 3,46-3,42 (m, 2H), 2,33-2,21 (m, 3H), 2,05-1,85 (m, 4H), 1,58-1,42 (m, 2H), 1.25-1.15 (m, 2H).

B. dimethylbicyclo [2.2.2] octane-1,4-dicarboxylate. To a solution of diisopropylamine (77 ml, 0.54 mol) in anhydrous THF (500 mL) was added n-butyllithium (210 mL, 0.53 mol, 2.5 M solution in hexanes) for 20 min at -78 ° C. The mixture was stirred at 0 ° C under a nitrogen atmosphere for 30 min.

To a mixture of dimethyl-1- (2-chloroethyl) -cyclohexane-1,4-dicarboxylate (116 g, 0.44 mol) and hexamethylphosphoramide (317 ml, 1.7 mol) in anhydrous THF (800 mL) was added freshly prepared lithium diisopropylamide ( prepared as described above) for 30 minutes at -40 ° C. The mixture was stirred for 2 hours at -78 ° C and then stirred overnight, leaving to warm at room temperature. The reaction mixture was added a saturated aqueous solution of ammonium chloride (200 ml) and the mixture was stirred for 10 min. The volatile solvents were removed by evaporation under reduced pressure. The aqueous layer was extracted with ethyl acetate (3 × 200 mL) and the combined extracts were washed with saturated brine (300 ml × 2) and dried over sodium sulfate. Concentration under reduced pressure gave a crude product,¹H-ЯМР (400 МГц, CDCl₃): Δ h / million 3.65 (s, 6H), 1.81 (s, 12H)..

C. 4- (Methoxycarbonyl) bicyclo [2.2.2] octane-1-carboxylic acid. A solution dimethylbicyclo [2.2.2] octane-1,4-dicarboxylate (58.0 g, 0.25 mol) in methanol (600 ml) was heated at reflux and then a solution of potassium hydroxide (9.8 g, 0.175 mol) in methanol (100 ml) and water (12 mL) for 30 min. The reaction mixture was refluxed for 24 hours and concentrated. The solid residue was diluted with water and extracted with ethyl acetate (200 ml × 2) to recover a certain amount of the starting material (22.0 g). The resulting aqueous layer was acidified to pH = 3 by adding hydrochloric acid and extracted with ethyl acetate (300 ml × 3). The combined organic layers were washed with saturated brine, dried over sodium sulfate and concentrated to give the product of the title (30.0 g, 0,¹Н-ЯМР (400 МГц, CDCl₃.) Δ h / million 3.65 (s, 3H), 1.81 (s, 12H); MS (ESI) m / z = 211,3 [M-H]^-.

D. Methyl 4-bromobicyclo [2.2.2] octane-1-carboxylate. To a suspension of 4- (methoxycarbonyl) bicyclo [2.2.2] octane-1-carboxylic acid (11.0 g, 51.8 mmol) in acetone (80 mL) was added aqueous sodium hydroxide (1 M, 51.8 mL, 51.8 mmol) and silver nitrate (8.8 g, 51.9 mol) in water (10 ml). The resulting residue was collected by filtration, washed with water, acetone and diethyl ether and dried in vacuo at 115 ° C for 4 hours. The resulting ((4- (methoxycarbonyl) bicyclo [2.2.2] octane-1-carbonyl) oxy) Silver (15.3 g, 47.9 mmol) was suspended in hexane (125 ml), followed by bromine (7.7 g, 48.1 mmol) for 30 min at room temperature. After complete addition, the reaction mixture was stirred at room temperature for another 30 min. The reaction mixture was filtered to remove solid, and the filter cake washed with hexane (150 ml × 4). The combined organic filtrates were washed with saturated aqueous sodium bicarbonate solution (150 ml × 2) and saturated brine (200 ml), then dried over magnesium sulfate. Concentration under reduced pressure gave a crude product which was purified by chromatography on a silica gel column (5% ethyl acetate in petroleum ether) to give the compound of the title (4.2 g, 0.17 mol, 33% yield for two steps ).¹H-ЯМР (400 МГц, CDCl₃): D ч. / Млн 3,64 (с, 3Н), 2,27-2,20 (м, 6Н), 1,98-1,94 (м. 6Н).

E. 4-hydroxybicyclo [2.2.2] octane-1-carboxylic acid. Methyl 4-bromobicyclo [2.2.2] octane-1-carboxylate (17.0 g, 69.0 mmol) was refluxed in 1.5 L of 1% aqueous solution of sodium hydroxide for 24 hours. After cooling, the reaction solution was acidified with hydrochloric acid (6N, 100 mL) and extracted with diethylether (6 × 500ml). The combined organic layers were dried over magnesium sulfate and concentrated to give the compound of the title (10.4 g, 61.1 mmol, yield: 89%) which was used in the next step without further purification; MS (ESI) m / z = 169,2 [M-H]^-.

F. Methyl 4-hydroxybicyclo [2.2.2] octane-1-carboxylate. To a solution of 4-hydroxybicyclo [2.2.2] octane-1-carboxylic acid (14 g, 82.4 mmol) in methanol (300 ml) was added concentrated sulfuric acid (1 mL). The mixture was refluxed for 10 hours and then concentrated. The residue was dissolved in water (100 ml) and the mixture was extracted with ethyl acetate (200 ml × 2). The combined organic phases were washed with saturated aqueous sodium hydrogencarbonate solution (100 ml), brine (100 ml) and dried over sodium sulfate. Concentration gave compound the title compound (14.5 g, yield 96%).¹Н-ЯМР (400 МГц, CDCl₃) D ч. / Млн 3,64 (с, 3Н), 1,96-1,89 (м, 6Н), 1,69-1,64 (м, 6Н).

G. Methyl 4-metoksibitsiklo [2.2.2] octane-1-carboxylate. To a solution of methyl-4-hydroxybicyclo [2.2.2] octane-1-carboxylate (8.9 g, 48 mmol) in anhydrous THF (150 mL) at -78 ° C was added n-butyllithium (23 mL, 57.5 mmol , 2.5 M solution in hexane) within 30 min, and then slowly added iodomethane (14 g, 98 mmol). The mixture was stirred at 60 ° C for 3 h and quenched by addition of saturated aqueous ammonium chloride solution (50 mL).

The resulting solution was concentrated and the solid residue was extracted with ethyl acetate (150 ml × 2). The organic layers were combined and washed with saturated brine, dried over magnesium sulfate and then concentrated. The solid residue was purified by chromatography on a silica gel column (10% ethyl acetate in petroleum ether) to give the product of the title (6.5 g, 67%).¹Н-ЯМР (400 МГц, CDCl₃) Δ hr. / Million 3.64 (s, 3H), 3.18 (s, 3H), 1,95-1,89 (m, 6H), 1.70-1.65 (m, 6H).

H. 4-Metoksibitsiklo [2.2.2] octane-1-carboxylic acid. Methyl 4-metoksibitsiklo [2.2.2] octane-1-carboxylate (6.5 g, 33 mmol) was refluxed in aqueous sodium hydroxide (5%, 150 ml) for 2 hours. After cooling, the reaction solution was acidified hydrochloric acid (6N, 50 mL) and extracted with ethyl acetate (100 ml × 2). The combined organic layers were dried over magnesium sulfate and concentrated to give compound the title compound (5.9 g, 32 mmol, yield 97%) which was used in the next step without further purification. MS (ESI) m / z = 183,2 [M-H]^-.

I. Benzyl (4-metoksibitsiklo [2.2.2] octan-1-yl) carbamate. To a solution of 4-metoksibitsiklo [2.2.2] octane-1-carboxylic acid (5.9 g, 32 mmol) in dioxane (80 mL) was added DIEA (8.3 g, 64.2 mmol), diphenylphosphoryl azide (13.2 g, 48 mmol) and phenylmethanol (17.3 g, 160 mmol). The mixture was stirred at 80 ° C overnight and then concentrated under reduced pressure. The solid residue was purified by chromatography on a silica gel column (5% methanol in DCM) to give the desired product. (9 g, 31 mmol, 96% yield). MS (ESI) m / z = 290,2 [M + H]⁺.

J. 4-Metoksibitsiklo [2.2.2] octan-1-amine hydrochloride. To a solution of benzyl (4-metoksibitsiklo [2.2.2] octan-1-yl) carbamate (9 g, 31 mmol) in methanol (150 mL) was added palladium on carbon (0.5 g, 10%). The reaction mixture was stirred at 50 ° C in a hydrogen atmosphere (50 psi. Inch) overnight and then filtered through celite. The filtrate was concentrated under reduced pressure. The solid residue was dissolved in hydrochloric acid solution (10% in methanol, 50 mL) and stirred for 2 hours at room temperature. The mixture was concentrated and the resulting solid suspended in THF (20 mL). The mixture was stirred at room temperature for 1 h, and the residue was collected and dried to give the desired product (3.8 g, 20 mmol, yield: 68%).¹Н-ЯМР (400 МГц, DMS-d₆) Δ hr. / Million 8.14 (br. S, 3H), 3.04 (s, 3H), 1,83-1,80 (m, 6H), 1,68-1,64 (m, 6H ); MS (ESI) m / z = 156,1 [M + 1]⁺.

C. 4 - ((1R, 3S) -3-hydroxycyclohexylamino) -2- (4-metoksibitsiklo [2.2.2] octan-1-ylamino) pyrimidine-5-carboxamide. To a solution of 4 - ((1R, 3S) -3-hydroxycyclohexylamino) -2- (methylsulfonyl) pyrimidine-5-carboxamide (1.2 g, 3.8 mmol; synthesis described herein) and of 4-metoksibitsiklo [2.2 .2] octane-1-amine (600 mg, 3.1 mmol) in NMP (12 mL) was added DIEA (1.03 g, 8 mmol). The resulting mixture was stirred at 130 ° C under microwave irradiation for 3 hours. The mixture was purified by reverse-phase column to give the desired product (230 mg, 0.6 mmol, 15.5% yield).¹Н-ЯМР (400 МГц, CDCl₃) Δ hr. / Million 8.70 (br. S., 1H), 8.08 (s, 1H), 5.40 (br. S., 2H), 5.01 (br. S, 1H) 3,99-3,96 (m, 1H), 3,75-3,70 (m, 1H), 3.19 (s, 3H), 2,37-2,34 (m, 1H), 2, 15-2,11 (m, 6H), 1,99-1,97 (m, 2H), 1,90-1,86 (m, 1H), 1,80-1,76 (m, 6H), 1,38-1,22 (m, 4H). MS (ESI) m / z = 390,2 [M + 1]⁺.

Example 58 2 - ((1R, 4R) -4-Gidroksiciklogeksilamino) -4- (3- (triftormetil) bicyclo [1.1.1] pentan-1-ylamino) pyrimidine-5-carboxamide

<img file="00000164.jpg" he="39" wi="53" img-format="tif" img-content="undefined" />

А. 2 - ((1R, 4R) -4-Гидроксициклогексиламино) -4- (3- (трифторметил) бицикло [1.1.1] пентан-1-иламино) пиримидин-5-карбоксамид. К 5 мл NMP раствора (2 - ((1R, 4R) -4-гидроксициклогексиламино) -4- (метилсульфонил) пиримидин-5-карбоксамида (445 мг, 1.416 ммоль)) добавляли гидрохлорид 3- (трифторметил) бицикло [1.1.1 пентан-1-амина (266 мг, 1.416 ммоль) и ДИЭА (0,494 мл, 2.83 ммоль). Реакционную смесь затем нагревали при температуре 90 ° С в течение ночи. ЖХ-МС показала, что масса целевого продукта имела доминирующий пик. Сырую реакционную смесь очищали непосредственно на полупрепаративной ВЭЖХ (способ: 5-80% ацетонитрил + 0,1% ТФУ в воде + 0,1% ТФУ). Фракции продукта объединяли и упаривали при пониженном давлении до объема &lt;5 мл. Вещество затем нейтрализовывали насыщенным бикарбонатом натрия и экстрагировали этилацетатом (2х). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The resulting solid was dissolved in methanol and was washed through the column StratoSpheres SPE PL-HCO3 MP-Resin, eluting with methanol. Evaporation of the solvent under reduced pressure gave 2 - ((1R, 4R) -4-hydroxycyclohexylamino) -4- (3- (trifluoromethyl) bicyclo [1.1.1] pentan-1-ylamino) pyrimidine-5-carboxamide. The substance was purified by silica gel chromatography (0-10% methanol in DCM during 1650 ml, 40 ml / min). The product fractions were combined and evaporated to dryness to give 2 - ((1R, 4R) -4-hydroxycyclohexylamino) -4- (3- (trifluoromethyl) bicyclo [1.1.1] pentan-1-ylamino) pyrimidine-5-carboxamide (135 mg , 0.35 mmol, 24.8% yield); The resulting solid was dissolved in methanol and was washed through the column StratoSpheres SPE PL-HCO3 MP-Resin, eluting with methanol. Evaporation of the solvent under reduced pressure gave 2 - ((1R, 4R) -4-hydroxycyclohexylamino) -4- (3- (trifluoromethyl) bicyclo [1.1.1] pentan-1-ylamino) pyrimidine-5-carboxamide. The substance was purified by silica gel chromatography (0-10% methanol in DCM during 1650 ml, 40 ml / min). The product fractions were combined and evaporated to dryness to give 2 - ((1R, 4R) -4-hydroxycyclohexylamino) -4- (3- (trifluoromethyl) bicyclo [1.1.1] pentan-1-ylamino) pyrimidine-5-carboxamide (135 mg , 0.35 mmol, 24.8% yield); The resulting solid was dissolved in methanol and was washed through the column StratoSpheres SPE PL-HCO3 MP-Resin, eluting with methanol. Evaporation of the solvent under reduced pressure gave 2 - ((1R, 4R) -4-hydroxycyclohexylamino) -4- (3- (trifluoromethyl) bicyclo [1.1.1] pentan-1-ylamino) pyrimidine-5-carboxamide. The substance was purified by silica gel chromatography (0-10% methanol in DCM during 1650 ml, 40 ml / min). The product fractions were combined and evaporated to dryness to give 2 - ((1R, 4R) -4-hydroxycyclohexylamino) -4- (3- (trifluoromethyl) bicyclo [1.1.1] pentan-1-ylamino) pyrimidine-5-carboxamide (135 mg , 0.35 mmol, 24.8% yield); The substance was purified by silica gel chromatography (0-10% methanol in DCM during 1650 ml, 40 ml / min). The product fractions were combined and evaporated to dryness to give 2 - ((1R, 4R) -4-hydroxycyclohexylamino) -4- (3- (trifluoromethyl) bicyclo [1.1.1] pentan-1-ylamino) pyrimidine-5-carboxamide (135 mg , 0.35 mmol, 24.8% yield); The substance was purified by silica gel chromatography (0-10% methanol in DCM during 1650 ml, 40 ml / min). The product fractions were combined and evaporated to dryness to give 2 - ((1R, 4R) -4-hydroxycyclohexylamino) -4- (3- (trifluoromethyl) bicyclo [1.1.1] pentan-1-ylamino) pyrimidine-5-carboxamide (135 mg , 0.35 mmol, 24.8% yield);¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 9.54 (s, 1H), 8.41 (s, 1H), 7,57-7,86 (m, 1H), 7.26-7.32 (m, 1H), 6,91-7,17 (m, 1H), 4.60 (d, J = 4,29 Hz, 1H), 3,49-3,73 (m, 1H), 3.35-3.46 ( m, 1H), 2.38 (s, 6H), 1.86 (d, J = 11,32 Hz, 4H), 1.26 (br s, 4H)..; MS (ESI) m / z 386,0 [M + 1]⁺.

Example 59: 4- (tert-butylamino) -2 - (((1 R, 3S) -3-gidroksiciklogeksil) amino) pyrimidine-5-carboxamide

<img file="00000165.jpg" he="29" wi="55" img-format="tif" img-content="undefined" />

A. 4- (tert-butylamino) -2 - (((1R, 3S) -3-gidroksiciklogeksil) amino) pyrimidine-5-carboxamide. K mixtures 4- (tert-butylamino) -2- (metilsulьfonil) pyrimidine-5-carboxamide (250 mg, 0.918 mmolь; synthesis described in the present description) and (1S, 3R) -3-aminociklogeksanola (138 mg, 1.2 mmolь; poluchennый how described in Tetrahedron: Asymmetry 15: 2051-2056 (2004)) in NMP (10 ml) dobavlяli DIЭA (374 mg, 2.9 mmolь). Poluchennuю smesь peremeshivali at 100 ° C nochi. Reakcionnuю smesь ochiщali with pomoщью preparativnoй VЭZHH with polucheniem celevogo product (212.2 mg, 0.69 mmolь, vыhod 75%).¹H-ЯМР (400 МГц, CDCl₃) Δ hr. / Million 8.86 (br. S, 1H), 8.12 (s, 1H), 5.53 (br. S, 3H), 3,93-3,91 (m, 1H), 3.88-3.82 (m, 1H), 2,27-2,25 (m, 1H), 1,92-1,85 (m, 3H), 1.47 (s, 9H), 1, 42-1,25 (m, 4H); MS (ESI) m / z = 308,2 [M + 1]⁺.

Example 60: 4- (bicyclo [1.1.1] pentan-1-ylamino) -2 - ((tetragidro-2H-pyran-4-yl) amino) pyrimidine-5-carboxamide

<img file="00000166.jpg" he="34" wi="46" img-format="tif" img-content="undefined" />

A. 4- (Bicyclo [1.1.1] pentan-1-ylamino) -2- (methylthio) pyrimidine-5-carbonitrile. To peremešannomu solution of 4-chloro-2- (methylthio) pyrimidine-5-carbonitrile (3.0 g, 16 mmol) in DMSO (20 ml) dobavlâli DIEA (6.2 g, 48 mmol) and hydrochloride bicyclo [1.1.1 ] pentan-1-amine (1.9 g, 16 mmol; recieved in accordance with Org. Lett., 13 (17): from 4746 to 4748 (2011)). Polučennuû peremešivali mix at 60 ° C in a week and after 2 h vylivali in water. Mixture ékstragirovali with ethyl acetate, and the associated organic layers dried over sodium sulfate bezvodnym, filʹtrovali and koncentrirovali syrogo with receipt of the product, which Cleansing via column chromatography on silica gel with (10% ethyl acetate in petroleumsulfonates eter) with receipt of celevogo product (3.5 g, 14 9 mmol, 93% output). MS (ESI) m / z = 233.2 [M + 1]⁺.

B. 4- (Bicyclo [1.1.1] pentan-1-ylamino) -2- (methylthio) pyrimidine-5-carboxamide. To a solution of 4- (bicyclo [1.1.1] pentan-1-ylamino) -2- (methylthio) pyrimidine-5-carbonitrile (3.45 g, 14.9 mmol) in DMSO (15 ml) solution Water dobavlâli perekisi vodoroda (8.4 g, 30%, 74.5 mmol) and Water Sodium gidroksida solution (12.4 ml, 6 mol / l, 74.5 mmol) at 0 ° C. Peremešivali mix at 50 ° C for 15 min and then quenched, dobavlââ water (30 ml). Sformirovavšeesâ tverdoe substance gathering place and dried under vacuum with receipt celevogo product (3.5 g, 14.0 mmol, 94% output). MS (ESI) m / z = 251.2 [M + 1]⁺.

C. 4- (Bicyclo [1.1.1] pentan-1-ylamino) -2- (methylsulfinyl) pyrimidine-5-carboxamide and 4- (bicyclo [1.1.1] pentan-1-ylamino) -2- (methylsulfonyl ) pyrimidine-5-carboxamide. mCPBA (4.3 g, 21 mmol) to a solution of Porcia dobavlâli 4- (bicyclo [1.1.1] pentan-1-ylamino) -2- (methylthio) pyrimidine-5-carboxamide (3.5 g, 14 mmol) in TGF (40 ml) at 0 ° C. Hod reactions kontrolirovali via tonkoslojnoj Chromatography. After 1 h reakcionnuû mix koncentrirovali. Crude product Cleansing recieved via column chromatography on silica gel with (5% methanol in DCM) with receipt of 3.1 g of mixture, the specified in the header. MS (ESI) m / z = 267.2 [M + 1]⁺/ 283.2 [M + 1]⁺.

D. 4- (Bicyclo [1.1.1] pentan-1-ylamino) -2 - ((tetragidro-2H-pyran-4-yl) amino) pyrimidine-5-carboxamide. To a mixture of 4- (bicyclo [1.1.1] pentan-1-ylamino) -2- (methylsulfinyl) pyrimidine-5-carboxamide, 4- (bicyclo [1.1.1] pentan-1-ylamino) -2- (methylsulfonyl) pyrimidine-5-carboxamide (300 mg) and hydrochloride tetragidro-2H-pyran-4-amine (181.5 mg, 1.32 mmol) in NMP (10 ml) dobavlâli DIEA (426 mg, 3.3 mmol). Polučennuû peremešivali blend at 100 ° C in the night a week. Thereafter reakcionnuû blend Cleansing via preparative HPLC with receipt celevogo product (221.3 mg, 0.73 mmol, 67% output) in the form of yellow powder.¹H-NMR (400 MHz, CD₃OD) δ hr. / Million 8.19 (s, 1H), 3,95-3,88 (m, 3H), 3,44-3,38 (m, 2H), 2.40 (s, 1H) 2.09 (s, 6H), 1,88-1,85 (m, 2H), 1.55-1.45 (m, 2H); MS (ESI) m / z = 304,2 [M + 1]⁺.

Example 61: 4- (bicyclo [1.1.1] pentan-1-ylamino) -2 - (((1 R, 3S) -3-gidroksiciklogeksil) amino) pyrimidine-5-carboxamide

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A. 4- (bicyclo [1.1.1] pentan-1-ylamino) -2- (methylsulfinyl) pyrimidine-5-carboxamide and 4- (bicyclo [1.1.1] pentan-1-ylamino) -2- (methylsulfonyl) pyrimidine 5-carboxamide. 3-Hlorbenzoperoksidnuû acid (4.27 g, 21 mmol) to a solution of Porcia dobavlâli 4- (bicyclo [1.1.1] pentan-1-ylamino) -2- (methylthio) pyrimidine-5-carboxamide (3.50 mg, 14 mmol, synthesis described in the Present Description) in the TGF (40 ml) at 0 ° C. Recieved peremešivali solution at 0 ° C in 1 h and a week after koncentrirovali in ponižennom pressure to the butter kotoroe Cleansing via column chromatography on silica gel with (5% methanol in DCM) with receipt of a mixture of 310 mg of 4- (bicyclo [1.1.1] pentan-1-ylamino) -2- (methylsulfinyl) pyrimidine-5-carboxamide and 4- (bicyclo [1.1.1] pentan-1-ylamino) -2- (methylsulfonyl) pyrimidine-5-carboxamide in the form of yellow Solid substances. MS (ESI) m / z = 267.2 [M + 1]⁺/ 283.2 [M + 1]⁺.

V. 4- (Bicyclo [1.1.1] pentan-1-ylamino) -2 - (((1 R, 3S) -3-gidroksiciklogeksil) amino) pyrimidine-5-carboxamide. To a mixture of 4- (bicyclo [1.1.1] pentan-1-ylamino) -2- (methylsulfinyl) pyrimidine-5-carboxamide and 4- (bicyclo [1.1.1] pentan-1-ylamino) -2- (methylsulfonyl) pyrimidine-5-carboxamide (300 mg) and (1S, 3R) -3-aminociklogeksanola (152 mg, 1.32 mmol; obtained as described in Tetrahedron: Asymmetry 15: 2051-2056 (2004)) in NMP (10 ml) dobavlâli DIEA (426 mg, 3.3 mmol). Polučennuû peremešivali blend at 100 ° C in the night a week. Cleansing Reakcionnuû mix via preparative HPLC with receipt celevogo product (230, 2 mg, 0.73 mmol, 66% output).¹H-NMR (400 MHz, CD₃OD) δ hr. / Million 8.29 (s, 1H), 3,91-3,89 (m, 1H), 3,69-3,62 (m, 1H), 2.50 (s, 1H) , 2,29-2,25 (m, 1H), 2.20 (s, 6H), 1.97-1.83 (m, 3H), 1,41-1,21 (m, 4H); MS (ESI) m / z = 318,2 [M + 1]⁺.

Example 62: 2- (Bicyclo [1.1.1] pentan-1-ylamino) -4 - ((1R, 3R) -3-Hydroxy-4,4-dimetilciklogeksilamino) pyrimidine-5-carboxamide

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A. N- (Bicyclo [1.1.1] pentane-1-yl) -5-bromo-4- (methylthio) pyrimidin-2-amine. To a stirred solution of 5-bromo-2-chloro-4- (methylthio) pyrimidine (1.0 g, 4.18 mmol) in NMP (10,0 mL) was added hydrochloride bicyclo [1.1.1] pentan-1-amine ( 749 mg, 6.26 mmol, prepared according to Org Lett, 13 (17):.. 4746-4748 (2011)) and DIEA (2.19 mL, 12.53 mmol). The mixture was stirred at 100 ° C for 16 hours and then the solvent was removed under reduced pressure. The solid residue was diluted with 100 ml ethyl acetate and 50 ml of a 1 M aqueous solution of sodium hydrogenphosphate. The layers was removed and the aqueous layer was extracted with 50 ml of ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give N- (bicyclo [1.1.1] pentan-1-yl) -5-bromo-4- (methylthio) pyrimidin-2-amine (1250 mg , 4.37 mmol, 105% yield) as a solid, which was used without further purification. MS (ESI) m / z 286,0 [M + 1]⁺and 288.0 [M + H]⁺.

V. 2- (Bicyclo [1.1.1] pentan-1-ylamino) -4- (methylthio) pyrimidine-5-carbonitrile. N- (bicyclo [1.1.1] pentan-1-yl) -5-bromo-4- (methylthio) pyrimidin-2-amine (1250 mg, 4.37 mmol), cinkovuû dust (71.4 mg, 1.092 mmol ), zinc cyanide (333 mg, 2.84 mmol), 1,1'-bis- (diphenylphosphino) ferrocene (196 mg, 0.349 mmol), tris (dibenzylideneacetone) dipalladij (0) (200 mg, 0.218 mmol) and DMA (8.35 ml) and obʺedinâli nagrevali in week overnight at 90 ° C in a nitrogen atmosphere. Reakcionnuû blend razbavlâli 125 ml of ethyl acetate and 50 ml of water and filʹtrovali through pad of Celite. The filtrate layers udalâli, and Water layer ékstragirovali 75 ml of ethyl acetate. Émirats étilacetatnye layers promyvali 2 × 50 ml nasyŝennym solevym solution, dried over magnesium sulfate bezvodnym, filʹtrovali koncentrirovali and to the butter. Syro Oil Cleansing via chromatography on silica gel (0% -30% ethyl acetate in Hexane).¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8,81-9,08 (m, 1H), 8,31-8,57 (m, 1H), 2.55-2.63 (m, 3H), 2.11 (s , 7H). MS (ESI) m / z 233,3 [M + 1]⁺.

C. 2- (Bicyclo [1.1.1] pentan-1-ylamino) -4- (methylthio) pyrimidine-5-carboxamide. To peremešivaemomu solution of 2- (bicyclo [1.1.1] pentan-1-ylamino) -4- (methylthio) pyrimidine-5-carbonitrile (566 mg, 2, 436 mmol) in DMSO (7 ml) dobavlâli 6 M solution Water gidroksida Sodium (2.030 ml, 12.18 mmol) and 30% Water solution of hydrogen perekisi (1.381 ml, 12.18 mmol) at 0 ° C. Mixture peremešivali then at 50 ° C for 30 min and then vylivali ledânuû in water (50 ml). Solid substances, å obrazovyvalisʹ, peremešivali bane to iced for 30 min, filʹtrovali, promyvali water and was then dried in a furnace in a week vakuumnoj overnight at 45 ° C with receipt of 2- (bicyclo [1.1.1] pentan-1-ylamino) - 4- (methylthio) pyrimidine-5-carboxamide (410 mg, 1.638 mmol, 67.2% output).¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8.41 (s, 1H), 7,03-8,34 (m, 2H), 2,43-2,48 (m, 1H), 2.35 (br. S., 3H), 2.09 (s, 6H). MS (ESI) m / z 251,3 [M + 1]⁺.

D. 2- (Bicyclo [1.1.1] pentan-1-ylamino) -4- (methylsulfinyl) pyrimidine-5-carboxamide. To peremešivaemomu solution of 2- (bicyclo [1.1.1] pentan-1-ylamino) -4- (methylthio) pyrimidine-5-carboxamide (410 mg, 1.638 mmol) in chloroform (39.0 ml) Porcia dobavlâli 3-phenyl- 2- (phenylsulfonyl) -1,2-oxaziridine (514 mg, 1.965 mmol). Recieved light yellow solution peremešivali at Ambient Temperature in week two nights in a nitrogen atmosphere. Reakcionnuû mix koncentrirovali in ponižennom pressure syrogo with receipt of the product in the form of white rigid substances. To these substances with solid dobavlâli with ethyl acetate (15 ml), and vzvesʹ peremešivali at week komnatnoj temperature in 1 h, filʹtrovali, promyvali ethyl acetate and dried in oven vakuumnoj for hours with receipt of 2- (bicyclo [1.1.1] pentan-1- ylamino) -4- (methylsulfinyl) pyrimidine-5-carboxamide (397 mg, 1,¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8,67-9,14 (m, 2H), 7,93-8,11 (m, 1H), 7.41-7.54 (m, 1H), 2,68-2 79 (m, 3H), 2,43-2,48 (m, 1H), 2.02-2.21 (m, 6H). MS (ESI) m / z 267,0 [M + 1]⁺.

E. 2- (Bicyclo [1.1.1] pentan-1-ylamino) -4 - ((1R, 3R) -3-Hydroxy-4,4-dimetilciklogeksilamino) pyrimidine-5-carboxamide. To peremešivaemoj suspensions 2- (bicyclo [1.1.1] pentan-1-ylamino) -4- (methylsulfinyl) pyrimidine-5-carboxamide (397 mg, 1.491 mmol) and a mixture of hydrochloride of (1R, 5R) -5-amino-2 , 2-dimetilciklogeksanola hydrochloride and (1S, 5S) -5-amino-2,2-dimetilciklogeksanola (348 mg, 1.938 mmol, synthesis described in the Present Description) in DMF (4.88 ml) dobavlâli DIEA (0.78 mL, 4.47 mmol), and reakcionnuû nagrevali mix to 90 ° C in a week overnight. Syru reakcionnuû vylivali mix in 60 ml of iced water. Receive vzvesʹ polučennogo Solid substances to within a ~ 1 h, filʹtrovali, promyvali water and dried for hours in an oven at vakuumnoj 45 ° C with receipt of a mixture of 2- (bicyclo [1.1.1] pentan-1-ylamino) -4- ( (1R, 3R) -3-Hydroxy-4, 4-dimetilciklogeksilamino) pyrimidine-5-carboxamide and 2- (bicyclo [1.1.1] pentan-1-ylamino) -4 - ((1S, 3S) -3-Hydroxy-4,4-dimetilciklogeksilamino) pyrimidine-5-carboxamide (481 mg, 1.392 mmol, 93% output). This substance otdelâli via preparative SFC hiralʹnyj Using ChralPak column AD-H, 250 x 30 mm ID with izokratičeskim 40% ethanol + 0.1% ammonium gidroksidom in SO₂ gradient at a flow rate of 120 ml / min and at 38 ° C. Isomer which was eluted faster, it was designated as Peak 1 and 132 mg (0.382 mmol) was obtained. Isomer which was eluted slower was labeled as peak 2 and 120 mg (0.349 mmol) was obtained.

Peak 1: ¹H-NMR (400 MHz, DMSO-d₆) Δ hr. / Million 8,85-9,12 (m, 1H), 8,14-8,44 (m, 1H), 7,63-7,90 (m, 1H), 4,47-4 63 (m, 1H), 3,76-3,96 (m, 1H), 3.08-3.23 (m, 1H), 2.43 (s, 1H), 2.04 (s, 6H ), 1.87-1.99 (m, 1H), 1,66-1,83 (m, 1H), 1,04-1,47 (m, 4H), 0.92 (s, 3H), 0.82 (s, 3H) MS (ESI) m / z 346,3 [M + 1]⁺.

Peak 2: ¹H-NMR (400 MHz, DMSO-d₆) Δ h. / M 8,88-9,07 (m, 1H), 8,25-8,45 (m, 1H), 7,57-7,90 (m, 1H), 4,46-4 59 (m, 1 H), 3,78-3,96 (m, 1H), 3,09-3,22 (m, 1H), 2,35-2,47 (m, 1H), 2.04 (s, 6H), 1,87-1,99 (m, 1H), 1,66-1,80 (m, 1H), 1,37-1,48 (m, 1H), 1,12-1 34 (m, 3H), 0,88-0,94 (m, 3H), 0,71-0,86 (m, 3H). MS (ESI) m / z 346,3 [M + 1]⁺.

By comparing the SAR forces with similar compounds of known absolute stereochemistry, as set forth herein, peak 1 was identified as 2- (bicyclo [1.1.1] pentan-1-ylamino) -4 - ((1S, 3S) -3 -hydroxy-4,4-dimethylcyclohexylamine) pyrimidine-5-carboxamide. Peak 2 was identified as 2- (bicyclo [1.1.1] pentan-1-ylamino) -4 - ((1R, 3R) -3-hydroxy-4,4-dimethylcyclohexylamine) pyrimidine-5-carboxamide.

analyzes

biochemical analyzes

A. Fluorescent assays time-resolved analysis of JNK1. 384-well fluorescence assays with a time resolution used for the control of JNK1 activity. Analysis JNK1 was performed in the following assay buffer: 50 mM HEPES, 10 mM MgCl₂, 1 mM EGTA, 2 mM DTT and 0.01% Tween 20. To initiate the reaction, 100 nM ULight ™ -labeled peptide 4EVR1 (Perkin-Elmer) and 5 mM ATP was stirred together with 500 pM JNK1 (Carna Biosciences) to give a total volume 20 ul in each well. The assay plate was incubated at room temperature for 1 h and quenched with a mixture of 30 mM EDTA and 4 nM Eu-anti-4EBP1, adding 20 .mu.l of stop solution to each well. The plate was read on a reader Perkin-Elmer Envision Reader.

Analysis JNK2. 384-well fluorescence assays with a time resolution was used to control the activity of JNK2. JNK2 analysis was performed in the following assay buffer: 50 mM HEPES, 10 mM MgCl₂, 1 mM EGTA, 2 mM DTT and 0.01% Tween 20. To initiate the reaction, 100 nM ULight ™ -labeled peptide 4EVR1 (Perkin-Elmer) and 5 mM ATP was stirred together with 500 pM JNK2 (Carna Biosciences) to give a total volume 20 ul in each well. The assay plate was incubated at room temperature for 1 h and quenched with a mixture of 30 mM EDTA and 4 nM Eu-anti-4EBP1, adding 20 .mu.l of stop solution to each well. The plate was read on a reader Perkin-Elmer Envision Reader.

B. Cascade analyzes Z'-LYTE^®

Анализ JNK1. Каскадный киназный анализ JNK1 Z 'LYTE^® was carried out in the following buffer: 50 mM HEPES at pH 7,5, 0,01% BRIJ-35, 10 mM MgCl₂, 1 mM EGTA and 1 mM DTT. Prepared in 10 .mu.l kinase reaction containing 1,81-7,25 ng JNK1, 25 ng inactive MARKARK2, 100 uM ATP and 2 uM Ser / Thr 04 Peptide. Analytical mixture was incubated at room temperature for 1 h then the reaction mixture was added to 5 .mu.l of developing reagent A (Invitrogen, PV3295) at a dilution of 1:. 512 and incubated at room temperature for another hour. The data is then read on a fluorescent plate reader and analyzed.

Анализ JNK2. Каскадный киназный анализ JNK2 Z 'LYTE^® was carried out in the following buffer: 50 mM HEPES at pH 7,5, 0,01% BRIJ-35, 10 mM MgCl₂, 1 mM EGTA and 2 mM DTT. Prepared in 10 .mu.l kinase reaction containing 0,38-1,5 ng JNK2, 100 ng inactive MARKARK2, 100 uM ATP and 2 uM Ser / Thr 04 Peptide. Analytical mixture was incubated at room temperature for 1 h then the reaction mixture was added to 5 .mu.l of developing reagent A (Invitrogen, PV3295) at a dilution of 1:. 512 and incubated at room temperature for another hour. The data is then read on a fluorescent plate reader and analyzed.

C. Radioactive tests

Analysis JNK1. Radioactive analysis JNK kinases were performed in 96-well format with a final volume of 100 .mu.l. The final concentration assay was 6.6 pM ATP (3x ATP Km), 2,64-5 mg / ml JNK1 and 100 ug / ml cJUN. JNK1 was diluted in the following dilution buffer (20 mM HEPES pH 7.6, 0.1 mM EDTA, 2,5 mM MgCl₂, 0.004% (w / v) Triton X100, 2 / ml Leupeptid, 20 mM B-glycerol phosphate, 0.1 mM Na₃VO₄ dithiothreitol) and then pre-mixed with cJun, diluted in substrate buffer (20 mM HEPES pH 7.6, 50 mM NaCl, 0,1 mM EDTA, 2,5 mM MgCl₂, 0.05% (w / v) Triton X100). The mixture JNK1 / cJun (85 .mu.l) was added to the inhibitor (5 l) diluted in 100% DMSO to give a final concentration of DMSO in the assay is 5% (vol. / Vol.). A mixture of enzyme, substrate and inhibitor were allowed to equilibrate at room temperature for 15 minutes. The reaction was started by adding 10 ul 10X ATP in kinase buffer (130 mM MgCl₂, 6 мМ дитиотреитол, 150 мМ паранитрофенилфосфат, 100 мкКю / мл y- [³³P] -ATP). The reaction was allowed carried out for 60 minutes and then the protein was precipitated by trichloroacetic acid (7.2% TCA final). After 30 minutes incubation with TCA, reaction products are collected onto glass microfilter 96-well plates (Millipore MAHF CIH60), using a Packard Filtermate. The residue was washed with phosphate buffered saline and the amount of phosphate incorporated in cJun quantified by stsintsiograficheskogo counter using Packard Topcount-NXT. All assays were performed under conditions in which phosphate incorporation was linear with respect to time and enzyme concentration. The IC₅₀ It was calculated as the inhibitor concentration at which the c-Jun phosphorylation is reduced to 50% of the control value.

Analysis JNK2. The assay was performed in 96-well format with a final volume of 100 .mu.l. The final concentration assay was 6.6 pM ATP (3x ATP Km), 0,2-0,53 g / ml JNK2 and 100 ug / ml cJUN. Diluted JNK2 next dilution buffer (20 mM HEPES pH 7.6, 0.1 mM EDTA, 2,5 mM MgCl₂, 0.004% (w / v) Triton X100, 2 / ml Leupeptid, 20 mM B-glycerol phosphate, 0.1 mM Na₃VO₄ dithiothreitol) and then pre-mixed with cJun, diluted in substrate buffer (20 mM HEPES pH 7.6, 50 mM NaCl, 0,1 mM EDTA, 2,5 mM MgCl₂, 0.05% (w / v) Triton X100). The mixture JNK2 / cJun (85 .mu.l) was added to the inhibitor (5 l) diluted in 100% DMSO to give a final concentration of DMSO in the assay is 5% (vol. / Vol.). A mixture of enzyme, substrate and inhibitor were allowed to equilibrate at room temperature for 15 minutes. The reaction was started by adding 10 ul 10X ATP in kinase buffer (130 mM MgCl₂, 6 mM dithiothreitol, 150 mM paranitrophenyl phosphate, 100 mkKyu / ml Y- [³³P] -ATP). Reactions allowed to carry lyatsya for 60 minutes and then the protein was precipitated by trichloroacetic acid (7.2% TCA final). After 30 minutes incubation with TCA, reaction products are collected onto glass microfilter 96-well plates (Millipore MAHF CIH60), using a Packard Filtermate. The residue was washed with phosphate buffered saline and the amount of phosphate incorporated in cJun quantified by stsintsiograficheskogo counter using Packard Topcount-NXT. All assays were performed under conditions in which phosphate incorporation was linear with respect to time and enzyme concentration. The IC₅₀ It was calculated as the inhibitor concentration at which the c-Jun phosphorylation is reduced to 50% of the control value.

cell assays

Analysis RAW2 64.7 phospho-cJun in whole cell. RAW264.7 cells were purchased from American Tissue Culture Collection and maintained in growth medium consisting of 90% vysokoglyukoznoy Dulbecco's Modified Dulbecco's method (Invitrogen), 10% fetal bovine serum (Hyclone) and 2 mM L-glutamine (Invitrogen ). All cells were cultured at 37 ° C in 95% air and 5% CO₂. Cells were plated at a density of 1,0 × 10⁵ cells per well in 96-well plate in 120 .mu.l of growth medium. The mother liquor diaminopyrimidine compound (30 mM) serially diluted with DMSO, then diluted in growth medium and added to each well as a 10x concentrated solution in a volume of 15 ul, were mixed and allowed to incubate with the cells. compound vehicle (DMSO) is maintained at a final concentration of 0.2% in all wells. After 30 minutes the cells were activated with lipopolysaccharide (ALEXIS Biochemicals) at a final concentration of 25 ng / ml. Lipopolysaccharide was added as a 10x concentrated solution in a growth medium and added in a volume of 15 l per well. Plates with cells were cultured for 1 h, then the cell medium was removed. The level of protein c-Jun, which is phosphorylated at serine in position 63, measured in accordance with the manufacturer's instructions for the kit lysis Kit-Phospho-c-Jun (Ser 63) to hold the whole cell assay (Meso Scale Discovery) except that the concentration of NaCl in lysis buffer was higher final concentration of 350 mM. The IC₅₀ calculated as the concentration diaminopyrimidine compound at which the level of phosphorylated c-Jun protein was reduced by 50% of the signal window. Specific compounds of Tables 1, 2 and 3 had a value of IC₅₀ from 0.01-30 uM in this assay.

Product Analysis IL-2 Jurkat T cells. Jurkat T cells (clone E6-1) are purchased from the American Tissue Culture Collection and maintained in growth medium consisting of RPMI medium 1640 containing 2 mM L-glutamine (Mediatech) with 10% fetal bovine serum (Hyclone) and pennitsilin /streptomycin. All cells were cultured at 37 ° C in 95% air and 5% CO₂. Cells were plated at a density of 1,0 × 10⁵ cells per well in 96-well plate in 120 .mu.l of growth medium. The mother diaminopyrimidine (20 mM) compound solution was diluted in growth medium and added to each well as a 10x concentrated solution in a volume of 15 ul and allowed preincubated with the cells for 30 min. compound vehicle (dimethylsulfoxide) is maintained at a final concentration of 0.2% in all samples. After 30 minutes the cells were activated with PMA (phorbol myristate acetate; final concentration 50 ng / ml) and PHA (phytohemagglutinin; final concentration 1 ug / ml). PMA and PHA were added as a 10x concentrated solution prepared in growth medium and added in a volume of 15 l per well. Plates with cells were cultured for 6 hours. The cells were pelleted by centrifugation and the medium was removed and stored at -20 ° C. Aliquots of media were analyzed according to the manufacturer's instructions set Human IL-2 Tissue Culture (Meso Scale Discovery). The IC₅₀ was calculated as the concentration of compound at which diaminopyrimidine IL-2 production was reduced to 50% of the signal window. Specific compounds of Tables 1, 2 and 3 had a value of IC₅₀ from 0.01-10 uM in this assay.

Animal models

Analysis pcJun and in vivo production of TNF-α, LPS induced rat or mouse. Males CD or C57Bl / 6 mice were obtained from the rats Charles River Laboratories, 7 weeks of age or 20 g weight, respectively, allowed for acclimatization for one week before use. Rats lateral tail vein is cannulated percutaneously 22-gage needle catheter under anesthesia breathing isoflurane and 20 .mu.g LPS (E. Coli 055: BS) and catheters were washed with 2.5 mL / kg of normal saline for injection. In mice 1 mg / kg LPS (E. Coli 055: BS) in saline was administered intraperitoneally in a volume of 200 .mu.l. Animals were diaminopyrimidine compound by oral gavage 15-180 min before LPS injection. Blood was collected by cardiac puncture 90 minutes or 2 hours after LPS administration in rats and mice, respectively, and the liver and epididymal fat were isolated for analysis pcJun, Using Mesoscale Discovery Platform. Plasma was prepared using tubes for separating lithium-heparin and frozen at -80 ° C before analysis. TNF-α levels were determined using a set of specific TNF-α ELISA for rats or mice (Mesoscale Discovery). The liver and epididymal fat were homogenised and sonicated in lysis buffer Mesoscale, determined by the composition of the protein (for detection of the BCA protein) levels and pcJun measured (Mesoscale Discovery). The ED The liver and epididymal fat were homogenised and sonicated in lysis buffer Mesoscale, determined by the composition of the protein (for detection of the BCA protein) levels and pcJun measured (Mesoscale Discovery). The ED The liver and epididymal fat were homogenised and sonicated in lysis buffer Mesoscale, determined by the composition of the protein (for detection of the BCA protein) levels and pcJun measured (Mesoscale Discovery). The ED₅₀ calculated as the dose of compound at which diaminopyrimidine TNF-α levels or pcJun decreased to 50% of the control value. Specific compounds of Tables 1, 2 and 3 had a value of ED₅₀ of 30-100 mg / kg in this assay.

Holinodefitsitnaya amino acids supplement induced nonalcoholic steatohepatitis (NASH) in the rat models. Male Wistar rats were obtained from Charles River Laboratories, 7 weeks of age, were allowed to acclimatize for one week before use. Rats were fed holinodefitsitnoy L-amino acid additive (CDAA) (Dyets Inc) for up to 12 weeks. The rats were administered by oral gavage diaminopyrimidine compound once or twice a day starting from the time reference of additives during between 2 and 12 weeks. At the time of completion of the study blood was collected by cardiac puncture and secreted by the liver and epididymal fat. Liver tissue was subjected to histology and number steatosis or fibrosis was quantitated by staining with H &amp; E (hematoxylin and eosin) or red picro Sirius. liver function analysis of liver enzymes examined, e.g., ALT and AST in plasma and serum. In addition, the levels of phospho-cJun in the liver was quantified by IHC, as described by Ma F. et. al. Lab Invest .; 89 (4): 470-84 (2009). The ED₅₀ calculated as the dose of compound at which diaminopyrimidine fibrosis, steatosis, liver enzymes and / or p-cJun levels decreased by 50% of control values. Specific compounds of Tables 1, 2 and 3 have, or have been shown to have the value of ED₅₀ of 30-100 mg / kg in this assay.

Model fibrosis in the bile duct ligation. mice Male BALB / c (22-24 g) were purchased from Charles River Laboratories, and allowed to acclimate for one week prior to surgery. Anesthetic Catamin (80-100 mg / kg) / xylazine (8 mg / kg), administered i.v., was used for the ligation surgery of the bile duct. Abdominal incision giving access to the bile duct, which was ligated to two 6.0 silk sutures, superimposed on bile duct rostral, associating it with the intestine. To close the abdominal wall and skin were used 3-0 vikrilny seam. After surgery, mice were administered daily 1 ml of lactated Ringer's solution subcutaneously and feed throughout the study. The test compounds were administered by oral gavage starting on the day after surgery. Research was stopped on day 14 after ligation of the bile duct. Blood was collected by cardiac puncture and serum was isolated for clinical analysis of liver function (ALT, AST and bilirubin). Liver tissue was harvested and histologically processed and stained with H &amp; E (hematoxylin and eosin) or red picro Sirius, and used to estimate the amount of inflammation, periportal hyperplasia, necrosis and fibrosis induced by bile duct ligation surgery. In addition, the levels of phospho-cJun in the liver was quantified by IHC, as described by Ma F. et. al. Lab Invest .; 89 (4): 470-84 (2009). Certain compounds of Table 1, 2 and 3 show, or, as shown, a statistically significant inhibition of inflammation, hyperplasia of periportal necrosis, fibrosis and / or levels of phospho-cJun in doses of 10-300 mg / kg QD or BID.

Fibrosis model with carbon tetrachloride. male mice C57BL / 6 obtained from Harlan, weighing 22-24 g on arrival and allowed to acclimate for one week prior to use. Fibrosis created intraperitoneal injection of CCl4 (0,75 ml / kg) in mineral oil (15% v / v CCl4 in mineral oil) 3 times a week. The animals were administered the compound diaminopyrimidine oral gavage 1 hour prior to the first injection of CCl4 and then daily or twice a day until the end of the study, 28 days later. At the end of the study blood was collected by cardiac puncture, and secreted by the liver. Liver tissue was subjected to histology and number steatosis or fibrosis quantitated after okrashinvaiya H &amp; E (hematoxylin and eosin) or red picro Sirius. Liver function was assessed analysis of liver enzymes, e.g., ALT and AST in the plasma or serum. Besides, -cJun phosphorus levels in the liver was quantified IHC, as described by Ma F. et. al. Lab Invest; 89 (4): 470-84 (2009). Certain compounds of Table 1, 2 and 3 show or may show a statistically significant inhibition of inflammation, hyperplasia of periportal necrosis, fibrosis levels and / or phosphorus-cJun at doses of 10-300 mg / kg QD or BID.

The skin model with bleomycin: Male or female DBA / 2 mice were obtained from Harlan, weight 22-24 g on arrival, and allowed to acclimate for one week prior to use. skin fibrosis induced by subcutaneous injection of bleomycin (0.5 mg / ml in a total volume of 100 ml) through day for 6 weeks in certain areas of the upper back. Animals were diaminopyrimidine compound by oral gavage for 1 hour prior to the first injection of bleomycin, followed by daily or twice daily until the end of the study, 3 or 6 weeks later. At the end of the study blood was collected by cardiac puncture and flayed. Skin subjected to histological analysis and the amount was determined by the thickness of the dermis after staining with H &amp; E (hematoxylin and eosin). Some tables 1 connection,

Lung model with bleomycin: Male C57BL / 6 mice were obtained from Charles River Laboratories, and the animals were allowed to acclimatize for at least 5 days. Deja animals on a 12 hour light / dark cycle, and at the age of about 8 weeks at the beginning of the study. Mice were lightly anesthetized with isoflurane and opened trachea. On day 0, injected with bleomycin (30 l, 0.05 U) into the trachea. After the injection of bleomycin wound was closed using clips, and the animal left restores. Prednisolone (positive control, were dosed i.p.), vehicle (p.o.) or compound diaminopyrimidine (p.o.) was administered from 30 minutes to 2 hours before the administration of bleomycin (prophylactic model) or 4 days after bleomycin administration (therapeutic model). Dose with a carrier, or a compound of diaminopyrimidine administered twice daily throughout the study, prednisolone dose was administered once per day. Mice were under daily observation to detect side effects of administration of the test substance, including effects on weight. Mice were sacrificed on day 13. Bronchoalveolar lavage was performed using 1 ml of phosphate buffered saline (PBS) and analyzed the total number of leukocytes. Results are expressed as the total number of cells obtained. Macrophages, eosinophils, neutrophils, lymphocytes were quantitatively analyzed in assays BALF. Proportion lungs were processed for histological examination by staining with H &amp; E (hematoxylin and eosin) or trihrom TUNEL. Sections with trichrome evaluated the severity of fibrosis as previously described (Ashcroft et al J. Clin Pathol 41...: 467-470 (1988)). Some of the compounds of Tables 1, 2 and 3 may show a statistically significant inhibition of lung fibrosis at dosages of 10-300 mg / kg QD or BID.

Lupus Model: Female NZB / NZW F1 mice were obtained from Jackson Laboratories between 4-12 weeks of age on arrival, and allowed to acclimate for one week prior to use and the development of spontaneous SLE-like disease. Animals were diaminopyrimidine compound by oral gavage at baseline and then daily or twice daily until the end of the study for up to 6 months. Blood was collected throughout the study and the serum was isolated to measure the occurrence of double-stranded DNA was included as a standard ELISA method and proteinmocheviny in urine. Some of the compounds of Table 1, 2 and 3 showed a statistically significant inhibition proteinmocheviny or double-stranded DNA at a dose of 10-300 mg / kg QD or BID.

UUO model of renal fibrosis: Male CD-IGS rats were obtained from Charles River Laboratories, weight approximately 150-160 g, and allowed to acclimate for one week prior to the study. The rats were anesthetized with ketamine / xylazine and the surgical area was sterilized with 70% ethanol and betadine. The ureter was opened through a midline incision and ligated twice using 5.0 silk suture at a distance of 1 cm from each other and between the cut ligation. The incision was closed using 3.0 silk suture and the animals allowed restores. Animals were diaminopyrimidine compound by oral gavage for 1 hour before the ligation of the ureter and then daily or twice daily until the end of the study within 7 days. At the end of the study blood was collected by cardiac puncture and kidneys were isolated. Kidneys were subjected to histological and morphological analysis and the amount of fibrosis quantitated after staining with H &amp; E (hematoxylin and eosin) or picro Sirius red stained alpha-smooth muscle actin. Some of the compounds of Table 1, 2 and 3 showed a statistically significant inhibition of fibrosis or staining alpha-smooth muscle actin at doses of 10-300 mg / kg QD or BID.

activity tables

Each compound in Table 1, 2 and 3 tersirovali in one or more biochemical assays and JNK1 activity was detected as described herein, all of the compounds with IC₅₀ below 10 microM in the assay, some of the compounds with IC₅₀ below 200 nM (activity level D), with some IC₅₀ between 200 nM and 800 nM (activity level C), with some IC₅₀ between 800 nM and 1 uM (activity grade B), and with the other IC₅₀ between 1 microM and 10 microM (activity level A).

Was cited a number of references, the disclosures of which are hereby incorporated herein by reference in its entirety.